What are the risks and benefits of using cell therapy that “turbocharges” the immune system to fight cancer?

Tags

CAR (Chimeric Antigen Receptor)-T

CAR-T cells and checkpoint inhibitors are currently the two major approaches to ‘turbocharge’ the immune system to fight cancer. While current generation of CAR-Ts have been found to work fairly well for blood cancers, especially B cell – Wikipedia cancers, I’ve argued elsewhere (1) this could well be because such approaches piggy-back on evolutionarily conserved mechanisms for T cell-B cell interactions which are the backbone of proper Adaptive immune system – Wikipedia function. However, such results haven’t yet been achieved for solid tumors where such approaches remain largely non-tumor specific, a major liability since it leaves open the possibility of fulminant tissue pathology and even autoimmunity.

In that respect, these two approaches aren’t necessarily an improvement on current cancer therapy mainstays, radiation and chemotherapy, both of which come with the well-known price tag of considerable collateral tissue damage. For example, CAR-Ts are increasingly hitting roadblocks in the form of life-threatening complications and even deaths in clinical trials and that too for other blood not even solid tissue cancers, so much so that leading cancer immunotherapy biotech, Juno Therapeutics – Wikipedia, recently mothballed its lead CAR-T therapy, for ALL (Acute lymphoblastic leukemia – Wikipedia) (2).

As-yet unattained, singular promise of Cancer immunotherapy – Wikipedia is potential to specifically target tumors, using tumor antigen-specific approaches. Major obstacles in achieving this goal remain

1. Identifying and validating tumor-specific antigens for various cancers.
2. Identifying, isolating and in vitro expanding tumor antigen-specific T cells, both CD4 and CD8.
3. Confirming tumor antigen-specificity of such T cells.

Steps 1 and 2 are extremely technologically challenging in basic immunological research itself so likely even more so in human immunology. As technological capabilities to a) identify tumor-specific antigens, and b) manipulate human T cells in vitro improve, chances of achieving a theoretical no-pain-all-gain goal could improve. Only such an approach would optimally harness the unique antigen-specific capacity of the adaptive immune system to specifically target and eliminate tumors without damaging normal tissues. A 2015 review (3) by Ton Schumacher and Robert D. Schreiber – Wikipedia is one of the most comprehensive in contextualizing the scope and potential of such as-yet unrealized tumor antigen-specific immunotherapy.

However, such an approach would likely still remain rather labor-intensive and artisanal since it’d remain individualized, personalized if you will. For one, mutations within tumors are increasingly recognized to be very idiosyncratic, varying not only from one patient to another but also from one part of a tumor to another. For another, as we already know from transplantation, T cell capacity for Graft-versus-host disease – Wikipedia necessitates autologous T cell infusions for cancer Rx (Autotransplantation – Wikipedia).

Bibliography

1. Tirumalai Kamala’s answer to Why is CAR T not very effective on solid tumors?

2. Xconomy, Alex Lash, March 1, 2017. After Trial Deaths, Juno Pivots and Scraps Lead CAR-T Therapy | Xconomy

3. Schumacher, Ton N., and Robert D. Schreiber. “Neoantigens in cancer immunotherapy.” Science 348.6230 (2015): 69-74. http://pmpathway.wustl.edu/files…

https://www.quora.com/What-are-the-risks-and-benefits-of-using-cell-therapy-that-turbocharges-the-immune-system-to-fight-cancer/answer/Tirumalai-Kamala

How do T-cells recognize foreign MHC molecules?

Tags

alloreactivity

Question details: How do T-cells recognize foreign MHC molecules (and get activated thereafter), when the T-cells are positively selected in the thymus to recognize only own MHC (and foreign peptide, and get activated thereafter)?

T cell development occurs in the Thymus – Wikipedia. T cells bind pMHC (peptides bound to Major histocompatibility complex – Wikipedia (MHC)). In fact they can bind peptides presented both by MHC expressed by cells in the Thymus – Wikipedia of the body in which they develop, MHC restriction – Wikipedia, as well as by MHC expressed in genetically non-identical transplants, for e.g. during Allotransplantation – Wikipedia (1) *. The latter phenomenon is called alloreactivity.

As-Yet Unresolved Conundrums About T cell Development

The remarkable feature about the repertoire of B and T cells bearing unique B-cell receptor – Wikipedia (BCRs) and TCRs is they’re generated blind, i.e., in the absence of foreknowledge of antigens and antigen-derived peptides a person may encounter and need to respond to through their lifetime. T cell repertoire refers to the diversity of clonotypic T cells expressing unique TCRs, clonotypic meaning when a given T cell divides it creates a multitude of T cells bearing that same unique somatically generated TCR (Somatic recombination – Wikipedia).

T cells aren’t ‘positively selected in the thymus to recognize only own MHC (and foreign peptide)‘. To understand how that’s not even possible, consider someone who gets infected with flu. Thymic selection of T cells that ‘recognize only own MHC and foreign peptide‘ implies that to even have flu-specific T cells in the first place, the thymus should express flu antigens to positively select T cells expressing flu-specific TCRs, and so on ad nauseam for every one of the millions of peptides derived from the multitude of different kinds of entities a body might encounter and need to prevail over in the course of a lifetime. Crux is the thymus needs to select myriad T cell specificities during thymic T cell development even though the body can’t predict what antigen-derived peptides and antigens it would encounter in future. After all, the human adaptive immune system does have T (and B) cells that can specifically recognize and bind any number and variety of them. A conundrum indeed in that mature T cells bind specifically to both peptides (the norm in any immune response) and MHC molecules (the case in ‘direct’ response to allogeneic transplants) that they “couldn’t” have encountered during their development in the thymus.

• How are TCR specificities selected during T cell development, as in the nature of the selecting thymic peptides. Cross-reactivity – Wikipedia is implicit in this process since clearly flu-derived peptides cannot have selected for a flu-specific T cell and so on.
• Alloreactvity only adds to the conundrum since T cells also appear capable of binding MHC molecules they’ve obviously never previously encountered as happens with genetically mismatched transplants.

MHC Restriction Of T cells

Two principal models explain MHC restriction of T cells (2, 3, 4, 5, 6, 7).

• One suggests the CD4 – Wikipedia and CD8 – Wikipedia co-receptors impose it during thymic development. These coreceptors are associated with the unique T cell Kinase – Wikipedia, Lck – Wikipedia and the idea is only those developing T cells, i.e., Thymocyte – Wikipedia, that succeed in binding MHC II or I with CD4 or CD8, respectively, could generate the full complement of signaling necessary within themselves to make it past this do or die bottleneck.
• The other postulates germline-encoded CDRs (Complementarity-determining region – Wikipedia), CDR1 and 2 within the TCR, need to bind distinct pockets within the MHC.

Though not mutually exclusive, these models make different predictions. For the first one it doesn’t matter whether the T cell repertoire contains TCRs that bind pMHC or not while the second one requires TCRs biased to bind MHC, regardless of its class (I or II) or allele.

T cells That Make It Through Thymic Development Appear Wired to Bind MHC

Back in 1971, Niels Kaj Jerne – Wikipedia hypothesized ‘parallel evolution’ (8) of MHC and the then-undiscovered T-cell receptor – Wikipedia (TCR). After all, how else to explain alloreactivity other than by coevolution of TCR and MHC (9)?

As a recent illustrative example, a clever in vitro cellular model from 2016 demonstrates that TCRs may indeed be hard-wired to bind MHC (10; see figure below from 11).

This 2016 study thus concurs with many previous experimental (mostly mouse and some human) studies that found some Germline – Wikipedia amino acid residues on TCR alpha and beta chains to be crucial for binding MHC (4, 12, 13, 14, 15).

Cumulative data thus allows to infer that T cell development in the thymus may be mainly to ensure that only T cells with a ‘functional’ TCR get through developmental bottlenecks to be released into the ‘periphery’, i.e., a TCR capable of binding pMHC and delivering a modicum of signals downstream into the T cell, just enough, not too much nor too little, a la Goldilocks.

How To Explain T cell Alloreactivity (Ability of T cells to bind and respond to MHCs other than those that selected them in the thymus)

TCRs clearly bind both MHC molecules and the peptides they present. Two prevalent models to explain alloreactivity largely differ in which is more important, recognition of the peptides that allo MHC present, peptide-centric model, or the MHC molecules themselves, MHC-centric model (see figure below from (1).

Structural and some functional data from different experimental studies (16, 17, 18, 19) support either model.

One mouse TCR (17) was found to assume different conformations to accommodate binding to selecting versus novel MHC and in that study interfering with TCR’s ability to engage the peptide had little effect, i.e., support for the MHC-centric model. One mouse TCR was found to assume different conformations to accommodate binding to different peptides (16), i.e., support for the peptide-centric model. Meantime studies with human TCRs and HLA class I (18, 19) also support the MHC-centric model. Rather than one or the other, both approaches likely play their part in physiology.

* Note this answer deliberately avoids using ‘self’ and ‘non-self’/‘foreign’, mainstay words in immunology that obfuscate rather than clarify. In the age of Human microbiota – Wikipedia they’re also obviously unsuitable.

Bibliography

1. Boardman, Dominic A., et al. “What Is Direct Allorecognition?.” Current Transplantation Reports (2016): 1-9. What Is Direct Allorecognition?

2. Feng, Dan, et al. “Structural evidence for a germline-encoded T cell receptor–major histocompatibility complex interaction’codon’.” Nature immunology 8.9 (2007): 975-983. https://www.researchgate.net/pro…

3. Dai, Shaodong, et al. “Crossreactive T Cells spotlight the germline rules for αβ T cell-receptor interactions with MHC molecules.” Immunity 28.3 (2008): 324-334. http://www.cell.com/immunity/pdf…

4. Garcia, K. Christopher, et al. “The molecular basis of TCR germline bias for MHC is surprisingly simple.” Nature immunology 10.2 (2009): 143-147. https://www.ncbi.nlm.nih.gov/pmc…

5. Garcia, K. Christopher. “Reconciling views on T cell receptor germline bias for MHC.” Trends in immunology 33.9 (2012): 429-436. https://www.ncbi.nlm.nih.gov/pmc…

6. Yin, Lei, et al. “T cells and their eons‐old obsession with MHC.” Immunological reviews 250.1 (2012): 49-60. https://www.ncbi.nlm.nih.gov/pmc…

7. Van Laethem, François, Anastasia N. Tikhonova, and Alfred Singer. “MHC restriction is imposed on a diverse T cell receptor repertoire by CD4 and CD8 co-receptors during thymic selection.” Trends in immunology 33.9 (2012): 437-441. https://www.ncbi.nlm.nih.gov/pmc…

8. Jerne, Niels Kaj. “The somatic generation of immune recognition.” European journal of immunology 1.1 (1971): 1-9. http://onlinelibrary.wiley.com/d…

9. Felix, Nathan J., and Paul M. Allen. “Specificity of T-cell alloreactivity.” Nature Reviews Immunology 7.12 (2007): 942-953.

10. Parrish, Heather L., et al. “Functional evidence for TCR-intrinsic specificity for MHCII.” Proceedings of the National Academy of Sciences 113.11 (2016): 3000-3005. http://www.pnas.org/content/113/…

11. Krovi, Sai Harsha, and Laurent Gapin. “Revealing the TCR bias for MHC molecules.” Proceedings of the National Academy of Sciences 113.11 (2016): 2809-2811. http://www.pnas.org/content/113/…

12. Huseby, Eric S., et al. “How the T cell repertoire becomes peptide and MHC specific.” Cell 122.2 (2005): 247-260. http://www.cell.com/cell/pdf/S00…

13. Marrack, Philippa, et al. “Evolutionarily conserved amino acids in TCR V regions and MHC control their interaction.” Annual review of immunology 26 (2008): 171. https://www.ncbi.nlm.nih.gov/pmc…

14. Scott-Browne, James P., et al. “Germline-encoded amino acids in the αβ T cell receptor control thymic selection.” Nature 458.7241 (2009): 1043. https://www.ncbi.nlm.nih.gov/pmc…

15. Adams, Jarrett J., et al. “Structural interplay between germline interactions and adaptive recognition determines the bandwidth of TCR-peptide-MHC cross-reactivity.” Nature immunology 17.1 (2016): 87-94. https://www.ncbi.nlm.nih.gov/pmc…

16. Reiser, Jean-Baptiste, et al. “Crystal structure of a T cell receptor bound to an allogeneic MHC molecule.” Nature immunology 1.4 (2000): 291-297. https://www.researchgate.net/pro…

17. Colf, Leremy A., et al. “How a single T cell receptor recognizes both self and foreign MHC.” Cell 129.1 (2007): 135-146. https://www.researchgate.net/pro…

18. Archbold, Julia K., et al. “Alloreactivity between disparate cognate and allogeneic pMHC-I complexes is the result of highly focused, peptide-dependent structural mimicry.” Journal of Biological Chemistry 281.45 (2006): 34324-34332. Alloreactivity between Disparate Cognate and Allogeneic pMHC-I Complexes Is the Result of Highly Focused, Peptide-dependent Structural Mimicry

19. Macdonald, Whitney A., et al. “T cell allorecognition via molecular mimicry.” Immunity 31.6 (2009): 897-908. https://www.researchgate.net/pro…

https://www.quora.com/How-do-T-cells-recognize-foreign-MHC-molecules/answer/Tirumalai-Kamala

How is it possible that a T Cell Receptor (TCR) recognises as few as 1-3 residues of the MHC-associated peptide?

Tags

Complementarity-determining region (CDR)3, Immunodominance, pMHC (peptide bound to MHC molecule), somatic gene rearrangement, VDJ recombination

Question details: In Basic Immunology, 5th Edition, it was mentioned that “each TCR recognizes as few as one to three residues of the MHC-associated peptide”. How is that possible while retaining specificity to the antigen? It seems to me that any single amino acid could be common to more than 1 peptide.

Short answer: Structural constraints on how many amino acid residues TCRs can bind on short peptide sequences include

• Several of the peptide’s amino acid residues are already engaged in binding firmly to an MHC (Major histocompatibility complex) molecule creating the pMHC (peptide bound to MHC molecule).
• At the same time the TCR also needs to bind some amino acid residues of the MHC molecule itself.

Different parts of the TCR bind peptide and MHC. The unique process of somatic nucleotide insertions and deletions makes the TCR’s Complementarity-determining region (CDR)3 region hypervariable and thus quite flexible and effective in binding a few conserved residues on a MHC-bound peptide. This feature also makes TCRs cross-reactive, i.e., capable of binding >1 unique pMHC.

Longer answer on theoretical basis for why it should be so and some data on how TCRs actually bind peptides

The adaptive immune system is predicated on the notion of anticipatory defense. CD4 and CD8 T cells express the alphabeta TCR, composed of two protein chains, alpha and beta. Each undergoes somatic gene rearrangement, specifically V(D)J recombination, i.e., nucleotide insertions and deletions at the V(D) J junctions in the Complementarity-determining region (CDR)3 regions of each chain of the TCR. This means each human body iterates from scratch its adaptive defense armamentarium, something that a 2015 immune parameter analysis of 210 healthy monozygotic twin pairs only confirms (1).

At first glance, this seems reasonable enough. After all, TCRs on CD4 and CD8 T cells have evolved to recognize and bind not whole protein molecules, ‘antigens’, but rather presented by MHC molecules, tiny pieces thereof, ‘peptides’, 12- to 20-mer (12-20 amino acids in length) in the case of CD4s, and 8- to 14-mer in the case of CD8s.

On second glance, this imposes a heavy burden on such a recognition system. Zooming in from larger structures to much smaller ones means the number of peptides presented to T cells by MHC class I and II molecules should be very large. Why should? Zooming in to such magnification simply exponentially increases the number of targets, i.e., peptides. If MHC molecules didn’t present as diverse of a peptide pool as possible from within a cell, missed pathogen-derived peptides become missed opportunities weakening the anticipatory potential of the adaptive immune system.

Given that TCRs bind short peptide sequences presented by MHC molecules, how could recognition be based on other than a handful of amino acid residues? Much of the rest of the peptide binds the MHC molecule. Peptide binding to MHC is itself a critical filtering event of great consequence in adaptive immunity. Antigen processing generates many peptides of varying lengths during protein digestion but only a handful succeed in making it past several bottlenecks to successfully and tightly bind MHC in such a way that they get presented on the cell surface, a feature called Immunodominance.

Why Most T cell Receptors (TCRs) Need To Be Inherently Cross-Reactive, Capable Of Binding >1 pMHC Complex

T cell receptors (TCRs) bind bits of both MHC and peptide. TCRs are hypothesized to have been evolutionarily selected to recognize and bind MHC. Thus, considering just the TCR engagement with the peptide cuts off too small a slice of the pie since outcome, TCR-mediated biochemical activation of T cells, depends on other critical factors,

• How the peptide is bound within the MHC, which in turn determines which of its amino acid residues are available to make contact with the TCR and how optimally that could happen.
• How the peptide is bound within the MHC also determines how optimally key anchor residues of the MHC molecule itself are available to bind the TCR.
• How optimally can T cell co-receptors CD3 (immunology), CD4 (for CD4+ T cells)/CD8 (for CD8+ T cells) bind MHC at the same time.

Corollary of the fact that TCRs recognize and bind peptides presented by MHC molecules is the need for correspondingly large repertoire of specific T cells, one specific enough to recognize and bind each peptide processed and presented by each MHC molecule. However, if each TCR bound only one specific peptide, a logical extension of the Clonal selection theory (2, 3), each individual would theoretically need >10^15 T cells. Why? Because the 20 amino acid alphabet predicates the possible number of peptides that could bind to MHC molecules to be in the range of 10^15 (4). But 10^15 monospecific T cells necessary for optimal anticipatory defense entails a body weight of >500kgs (4), clearly and simply a physical impossibility, something that Don Mason already demonstrated in 1998 with his absurd mouse cartoon (see below from 5).

Given the constraint that there can only be far fewer T cells with unique TCRs compared to the potential diversity of possible unique pMHC complexes, no surprise TCRs tend to be cross-reactive, i.e., capable of binding >1 pMHC complex. An elegant 2014 experimental study found each of 5 different mouse and human TCRs even capable of binding >100 different peptides presented by one MHC molecule (6). Thus far crystal structures of ~120+ TCR- pMHC complexes have been published. One of the most striking observations of such crystal structures is the tremendous flexibility in how TCRs bind to pMHC (7). Rather than binding unique peptides, a given TCR can bind many but TCR binding’s supposed to be very specific. Cross-reactivity is antithetical to specificity. Can the two be reconciled? Yes, by the fact that the common thread linking cross-reactive peptides that bind a given TCR is the presence of conserved motifs, i.e., one, two, three or more conserved residues at specific TCR-binding positions (see quote, emphasis mine, and figure below from 6).

‘TCR cross-reactivity is not achieved by each receptor recognizing a large number of unrelated peptide epitopes but rather through greater tolerance for substitutions to peptide residues outside of the TCR interface, differences in residues that contact the MHC, and relatively conservative changes to the residues that contact the TCR CDR loops. The segregation of TCR recognition and MHC binding allows for TCRs to simultaneously accommodate needs for specificity and cross-reactivity.’

Thus, this example shows that even though peptides like 2A and MCC are very different in their sequences, both successfully bind the same TCR 2B4 because the process of somatic nucleotide insertions and deletions makes the region that primarily makes contact with a peptide, the TCR’s CDR3 region, hypervariable. This endows TCRs with the capacity to be quite flexible in accommodating different peptide sequences and also be able to bind firmly by contacting only a handful of conserved residues on any given MHC-bound peptide.

Human epidemiological studies reveal the implications of T cell recognition being the way it is. A relatively obscure set of data epitomize not only the extent of T cell cross-reactivity but also suggest that such functionality enables a vast, connected immunoprotective landscape against disparate entities ranging from bacteria to virus to cancer.

~85% of malignant melanocytes express an antigen called HERV-K-MEL (8, 9, 10), product of a pseudo-gene incorporated in the HERV-K env gene. HERV (Human Endogenous retrovirus) in turn are endogenous retroviruses incorporated into the human genome over millions of years. Acquired between 3 and 6 million years back, HERV-K are the latest family (11), making them the only HERVs still capable of replicating in the human population within the last few million years. HERV-K appears to be involved in several stages of melanoma formation (12, 13, 14).

Spontaneous melanoma regressions have occasionally been reported in the literature, suggesting effective anti-melanoma immune responses occur in nature. But what are the coordinates of such immunity? Taking a leaf out of William Coley and his Coley’s toxins, the European Organization for Research and Treatment of Cancer (EORTC) established the Febrile Infections and Melanoma (FEBIM) working group, tasked to explore how prior infectious diseases and vaccines influenced melanoma risk.

Their studies thus far suggest the Tuberculosis (TB) BCG vaccine, the Vaccinia vaccine against small pox and the 17D Yellow fever vaccine provide some degree of protection against melanoma (15, 16, 17).

What could possibly link such disparate characters as BCG, Vaccinia, Yellow fever and Melanoma and what connects this story to TCRs and peptides? Turns out each of these really disparate agents, a bacterium and two unrelated viruses, express peptides with high sequence homology to the melanoma HERV-K-MEL peptide (see below from 18).

BCG, vaccinia and yellow fever vaccines are of course expected to induce specific immune responses against themselves. However, given they express proteins with high sequence homology, vaccine-specific cytotoxic CD8+ and helper CD4+ T cells would also include those cross-reactive to melanoma HERV-K-MEL peptide. This could prevent melanoma development in those vaccinees who retain robust memory immune responses against this cross-reactive peptide.

Such phenomena may underlie the observation that certain live vaccines like BCG and measles can protect against unrelated pathogens and even reduce rates of all-cause mortality (19, 20). And as more microbiota-immunity interactions get mined, such examples that at present seem unanticipated will become more commonplace.

Bibliography

1. Brodin, Petter, et al. “Variation in the human immune system is largely driven by non-heritable influences.” Cell 160.1 (2015): 37-47.

2. Jerne, Niels K. “The natural-selection theory of antibody formation.” Proceedings of the National Academy of Sciences 41.11 (1955): 849-857. http://www.pnas.org/content/41/1…

3. Jerne, Niels Kaj. “The somatic generation of immune recognition.” European journal of immunology 1.1 (1971): 1-9.

4. Sewell, Andrew K. “Why must T cells be cross-reactive?.” Nature Reviews Immunology 12.9 (2012): 669-677. http://www.tcells.org/scientific…

5. Mason, Don. “A very high level of crossreactivity is an essential feature of the T-cell receptor.” Immunology today 19.9 (1998): 395-404.

6. Birnbaum, Michael E., et al. “Deconstructing the peptide-MHC specificity of T cell recognition.” Cell 157.5 (2014): 1073-1087. http://www.cell.com/cell/pdf/S00…

7. Rudolph, Markus G., Robyn L. Stanfield, and Ian A. Wilson. “How TCRs bind MHCs, peptides, and coreceptors.” Annu. Rev. Immunol. 24 (2006): 419-466. http://nfs.unipv.it/nfs/minf/dis…

8. Kölmel, K. F., O. Gefeller, and B. Haferkamp. “Febrile infections and malignant melanoma: results of a case-control study.” Melanoma research 2.3 (1992): 207-212

9. Schiavetti, Francesca, et al. “A human endogenous retroviral sequence encoding an antigen recognized on melanoma by cytolytic T lymphocytes.” Cancer research 62.19 (2002): 5510-5516. https://www.researchgate.net/pro…

10. Grange, John M., et al. “Can prior vaccinations against certain infections confer protection against developing melanoma?.” Medical Journal of Australia 191.9 (2009): 478. http://citeseerx.ist.psu.edu/vie…

11. Sverdlov, Eugene D. “Retroviruses and primate evolution.” Bioessays 22.2 (2000): 161-171.

12. Muster, Thomas, et al. “An endogenous retrovirus derived from human melanoma cells.” Cancer research 63.24 (2003): 8735-8741. https://www.researchgate.net/pro…

13. Serafino, A., et al. “The activation of human endogenous retrovirus K (HERV-K) is implicated in melanoma cell malignant transformation.” Experimental cell research 315.5 (2009): 849-862. https://www.researchgate.net/pro…

14. Singh, Sarita, et al. “The role of human endogenous retroviruses in melanoma.” British Journal of Dermatology 161.6 (2009): 1225-1231.

15. Grange, John M., Bernd Krone, and John L. Stanford. “Immunotherapy for malignant melanoma–tracing Ariadne’s thread through the labyrinth.” European Journal of Cancer 45.13 (2009): 2266-2273.

16. Krone, Bernd, et al. “Protection against melanoma by vaccination with Bacille Calmette-Guerin (BCG) and/or vaccinia: an epidemiology-based hypothesis on the nature of a melanoma risk factor and its immunological control.” European Journal of Cancer 41.1 (2005): 104-117.

17. Mastrangelo, G., et al. “Does yellow fever 17D vaccine protect against melanoma?.” Vaccine 27.4 (2009): 588-591.

18. Cegolon, Luca, et al. “Human endogenous retroviruses and cancer prevention: evidence and prospects.” BMC cancer 13.1 (2013): 1. http://bmccancer.biomedcentral.c…

19. Goodridge, Helen S., et al. “Harnessing the beneficial heterologous effects of vaccination.” Nature Reviews Immunology (2016).

20. Muraille, Eric. “The Unspecific Side of Acquired Immunity Against Infectious Disease: Causes and Consequences.” Frontiers in microbiology 6 (2015). https://www.ncbi.nlm.nih.gov/pmc…

https://www.quora.com/How-is-it-possible-that-a-T-Cell-Receptor-TCR-recognises-as-few-as-1-3-residues-of-the-MHC-associated-peptide/answer/Tirumalai-Kamala

Why is chimeric antigen receptor better than just injecting anti-CD19 antibodies? Since our natural killer cells can kill the cells attached with antibodies via antibody-dependent cell-mediated cytotoxicity.

Tags

Antibody-dependent cell-mediated cytotoxicity (ADCC), CD19, Chimeric antigen receptor (CAR), NK (natural killer) cell

Selectively getting rid of B cells is the therapeutic goal with many Leukemia and Lymphoma. It stands to reason that anti-CD19 antibodies would target B cell, which ~ exclusively and specifically express the CD19 molecule. In turn, anti-CD19 antibody-bound B cells are the target of Natural killer cell-mediated Antibody-dependent cell-mediated cytotoxicity, i.e., how antibodies that specifically bind to B cells could be used to get rid of them in B cell malignancies.

In practical terms, the success of such an antibody-mediated approach depends on the antibody’s Biological half-life within the body. Since much of the injected Antibody is simply eliminated, not all of the injected bolus is going to be therapeutically useful. This is why such Rx approaches typically require multiple shots.

On the other hand, Chimeric antigen receptor (CAR) essentially endows a T cell with additional Monoclonal antibody -like functionality. Here, such antibody-like specificity is ‘grafted’ onto the T cell by genetically engineering it to express a CAR that specifically binds the CD19 molecule expressed on the surface of B cells.

Even if, much like injected antibodies, some or many of such genetically engineered CAR-T cells are simply eliminated from the body shortly after injection, cells can replicate but molecules like antibodies can’t. Essentially CAR-T cells can a) replicate in the body to make more copies of themselves, and b) thus stick around longer. Thus, the CAR-T cell approach to target malignant B cells is more effective because it uses a replication-capable cell compared to antibodies which can’t replicate.

https://www.quora.com/Why-is-chimeric-antigen-receptor-better-than-just-injecting-anti-CD19-antibodies/answer/Tirumalai-Kamala

Why does antibody play no role in defending against tuberculosis?

Tags

Aharona Glatman-Freedman, Albert Calmette, Arturo Casadevall, Edward Livingston Trudeau

Role of antibodies and the cells that synthesize them, B cell, in protection against TB is a really important yet woefully neglected question. Is it even true Antibody has no protective role against TB (Tuberculosis)? The problem is a 100+ year old dogma that antibodies don’t protect against TB disease has held sway since the early 20th century. This created a scientific culture in TB research that rendered the idea of a protective role for antibodies against TB disease scientifically unpopular and stymied a rational, rigorous and systematic effort to explore their role in TB disease and resistance. How did this dogma get established and why does it dominate so? We need to dip a bit into history to understand that.

How The Outdated And Likely Wrong Dogma That Antibody Is Unprotective Against TB Disease Got Established

In the late 19th and early 20th centuries, efforts to treat TB disease using antibodies proved inconclusive. In those early days of microbiology ‘Serum Therapy’ (Antiserum) was the practical approach to assess whether or not antibody could be protective against a microbial disease. This entailed taking serum from an animal infected with a microbe and injecting it into a healthy one, and then challenging it with that same microbe. The liquid portion of blood after it clots, serum contains circulating antibodies, and serum therapy was found to prevent disease by microbes such as Streptococcus pneumoniae (causes pneumococcal pneumonia) and Neisseria meningitidis (causes meningitis).

Experiments also showed serum therapy worked with ‘immune’ but not ‘non-immune’ serum, i.e., only from serum obtained from animals injected with the specific microbes. Immune serum was thus functionally different from non-immune, meaning infection had induced some circulating component(s) with the capacity to prevent the same infection in uninfected, i.e., naive, animals. In the case of humans, immune serum was typically obtained from a convalescent, i.e., someone who’d successfully recovered from a natural infection. Serum therapy exists even today in the form of rabies immunoglobulin injected in people believed to have been bitten by a rabid animal.

Did serum therapy work against TB Disease? Short answer, no. According to an extremely detailed and thorough 1998 review by Aharona Glatman-Freedman and Arturo Casadevall, several attempts to successfully use serum therapy against TB disease in cow, donkey, horse and sheep were published between 1895 to 1934 (1).

Upshot? Unlike for microbes such as S. pneumoniae and N. meningitidis where serum therapy clearly worked, results were scatter-shot and all over the place with TB disease. With no consensus to support it, serum therapy thus fast faded from the TB scene. Science culture also played its role in this demise. After all, science doesn’t happen in a vacuum and ideas that dominate over time tend to ensue from individuals who dominate the field in their time. In those days the likes of Albert Calmette, Edward Livingston Trudeau dominated the TB field and they strongly believed that cells, i.e., Cell-mediated immunity, rather than antibodies, i.e., Humoral immunity, were important in controlling chronic TB disease, a situation they explicitly contrasted with acute S. pneumoniae and N. meningitidis diseases.

Let’s remember that back in those days little was known about the immune system. But given the human wont to classify, even back then cells could be easily differentiated from body fluids. Thus, even with the limited technology of those days, humoral, i.e., fluid-based, immunity was separable from cellular, i.e., cell-based, immunity. Common understanding is that humoral immunity means antibodies. Of course, this terminology was established long before T and B cells were discovered and long before the latter were identified as the source of antibodies. Separating humoral from cellular immunity, this absurd terminology representing truly outdated ideas persists even into our times, absurd because the former, humoral, is a product of the latter, cellular, specifically B cells.

Thus, dominated by early 20th century ideas of the kinds of immune responses deemed effective or ineffective against it, TB and immune system research proceeded to develop on parallel paths. As B and T cell were discovered in the 1950s to 1970s, and work continued apace to understand how they developed and functioned, this information was incorporated into the TB field on top of the pre-existing dogma that antibodies played no protective role against TB.

The choice to separate immune responses effective against TB disease from those effective against bacteria like S. pneumoniae and N. meningitidis also became premised on the distinction that TB disease’s causative agent, Mycobacterium tuberculosis (MTB), is an intracellular bacterium while the latter are extracellular. And of course, by then the idea that antibodies could be effective against entities residing inside cells had quickly become heresy.

Thus, as others took over the reins of TB research in the mid to late 20th century, the dogma persisted, with primacy accorded not to B cells and antibodies but rather to the phagocyte, Macrophage, the cell considered to be the primary site of MTB infection and growth, and to the T helper cell, the cell that should engage and guide these infected cells to exterminate their cargo of ingested mycobacteria. Succeeding generations of TB researchers continued disproportionately mining these same well-trod furrows while neglecting other aspects of the immune system, especially B cells and antibodies.

Another reality of science culture is that ideas that counter the dominating dogma are less likely to be funded and thus less likely to be studied. This is not to say that role of antibodies in TB stopped being studied. Just that focus of such studies became primarily technical as in efforts to develop serologic tests for TB disease diagnosis while B cell and antibody’s roles in helping establish or prevent TB disease remained a sparse and niche field that continued to yield contradictory results.

Some Data From More Recent Human Studies Support Roles For B Cells And Antibodies In Protection Against TB Disease

• Patients with TB disease among a Mexican Totonaca Indian population had better outcome if they had circulating anti-TB antibodies directed against the specific MTB antigen, Ag85 (2).
• Serum samples from healthy volunteers given two intradermal BCG vaccinations 2 months apart contained specific anti-MTB antibodies that demonstrated two critical protective features (3)
  • Enhanced the ability of neutrophils and monocytes/macrophages to inhibit MTB’s growth within them.
  • Enhanced proliferation of interferon-gamma secretion by MTB-specific CD4 and CD8 T cells. Interferon gamma is considered to be a critical cytokine for instructing infected macrophages and other phagocytes to turn on the biochemical machinery capable of killing intracellular mycobacteria.

Basis For Reconsidering Protective Roles For B Cells And Antibodies Against TB Disease

The absurdly reductionist view that an intracellular MTB is beyond the reach of antibodies overlooks the many pathways by which antibodies could still modify outcomes of such infections, ranging from engaging Fc receptor on the infected cell’s surface to Opsonin to Complement system activation, not to mention the many ways B cells could hep effect protection (see figures below from 4, 5 for some additional details). Such antibody-MTB engagement could

• Enhance MTB’s uptake by Phagocyte in a manner that enhances their killing.
• Enhance the capacity of MTB-specific T cells to secrete Cytokine capable of helping infected macrophages and other phagocytes turn on the biochemical machinery capable of killing intracellular mycobacteria they ingested.

Another research avenue grievously overlooked in TB-antibody research is the role of anti-MTB antibodies present in locations other than blood. TB is an airborne infection acquired through inhalation of MTB-laden aerosol droplets expelled by a person with active TB disease. It thus enters the body through the airways and indeed lung tissue is its primary target. Thus, the first cell types and pertinently, immune cell types it encounters are associated with respiratory mucosal membranes, i.e., Mucosal immunology. In that regard, one of the most neglected aspects in TB research is the potential role of mucosa-associated Immunoglobulin A antibodies in protecting against TB, a major oversight since the vast bulk of TB-antibody studies such as they are focus on circulating, i.e., blood-associated, anti-TB antibodies.

Bibliography

1. Glatman-Freedman, Aharona, and Arturo Casadevall. “Serum Therapy for Tuberculosis Revisited: Reappraisal of the Role of Antibody-Mediated Immunity againstMycobacterium tuberculosis.” Clinical Microbiology Reviews 11.3 (1998): 514-532. Reappraisal of the Role of Antibody-Mediated Immunity againstMycobacterium tuberculosis

2. Sanchez-Rodriguez, C., et al. “An IgG antibody response to the antigen 85 complex is associated with good outcome in Mexican Totonaca Indians with pulmonary tuberculosis.” The International Journal of Tuberculosis and Lung Disease 6.8 (2002): 706-712. http://www.ingentaconnect.com/co…

3. De Valliere, S., et al. “Enhancement of innate and cell-mediated immunity by antimycobacterial antibodies.” Infection and immunity 73.10 (2005): 6711-6720. Enhancement of Innate and Cell-Mediated Immunity by Antimycobacterial Antibodies

4. Rao, Martin, et al. “B in TB: B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis.” Clinical Infectious Diseases 61.suppl 3 (2015): S225-S234. B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis

5. Achkar, Jacqueline M., John Chan, and Arturo Casadevall. “B cells and antibodies in the defense against Mycobacterium tuberculosis infection.” Immunological reviews 264.1 (2015): 167-181. B cells and Antibodies in the Defense against Mycobacterium tuberculosis infection

https://www.quora.com/Why-does-antibody-play-no-role-in-defending-against-tuberculosis/answer/Tirumalai-Kamala

How would our lymphocytes recognize a new antigen when none of our lymphocytes have the appropriate receptor?

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Cross-reactivity

Answer applies to both T and B cells. Briefly? Cross-reactivity (Its Wikipedia page is better ignored).

Slightly longer answer: Clonal expansion and antigen-specific receptors are hallmarks of T and B cells. Tolerance is a developmental process which deletes developing T and B cells whose receptors bind self-antigens with strong affinity. Following this critical checkpoint, mature T and B cells circulate within the body. Per textbook definition, each of these T and B cells bears a unique receptor that binds a unique antigen. That’s certainly true but only partially so. Cross-reactivity is the piece that completes it.

Cross-reactivity means each unique T cell (TCR) or B cell (BCR) receptor has the capacity to bind a range of related antigens, i.e., it’ll bind some of them with very high affinity, others with much lower, but bind them all it will. This is the adaptive immune system’s way of hedging its bets to ensure that circulating T and B cells can more or less bind whatever antigen comes their way. In other words, TCRs and BCRs are promiscuous, capable of binding more than one antigen. Scope for cross-reactivity is much more vast in the case of the T cell since its receptors don’t directly bind an antigen but rather only a tiny piece of it, the peptide epitope, presented within an MHC molecule (See figure below from 1).

Similar principle applies to B cell receptors (BCRs) (See figure below from 2) and their antigen-binding sites, Paratope.

Bibliography

1. Sewell, Andrew K. “Why must T cells be cross-reactive?.” Nature Reviews Immunology 12.9 (2012): 669-677. http://www.tcells.org/scientific…

2. Kieber-Emmons, Thomas, et al. “Carbohydrate-mimetic peptides for pan anti-tumor responses.” Frontiers in immunology 5 (2013): 308-308. https://www.researchgate.net/pro…

https://www.quora.com/How-would-our-lymphocytes-recognize-a-new-antigen-when-none-of-our-lymphocytes-have-the-appropriate-receptor/answer/Tirumalai-Kamala

What are the most exciting developments in the field of immunology?

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Cancer Immunotherapy, César Milstein, Coley's toxins, Georges J. F. Köhler, Kefauver Harris Amendment, Tumor Immunology, William Coley

Hands down, cancer immunotherapy is one of the most exciting ones. News media reports on blockbuster cancer immunotherapy results are thick and fast these days. A newcomer could be forgiven for thinking such a close overlap between cancer and immunology has always been par for the course but nothing could be further from the truth. As recently as the 1970s, an immunologist choosing to study immune responses against tumors was committing career suicide. Instead then tumor immunology was a ‘a seedy intellectual neighborhood of fantasy and wishful thinking, a landscape littered with the hulks of abandoned hypotheses and charred reputations‘ (1).

20th century prospects of immune treatments for cancer started out on a very different note. Hardly anything known about immune function, yet William Coley had spectacular success treating a great variety of tumors in thousands of patients using Coley’s toxins, a mish-mash of bacterial cultures and toxins he called Mixed Bacterial Vaccine (MBV). His daughter painstakingly tracked down many of the patients he treated, showing they survived for years, even 88 years in one case (1). All this with just Coley’s MBV, no surgery or radiation. But after his death, MBV Rx rapidly faded.

The 1961 thalidomide tragedy inspired the Kefauver Harris Amendment, i.e., stricter scrutiny for new Rx. This changed regulatory landscape incentivized patentable products for drug licensing. A natural substance, MBV wasn’t patentable. In the vacuum, chemotherapy and radiotherapy quickly rose to dominate from the 1960s. At the same time, knowledge of immune responses improved by leaps and bounds. Yet such knowledge only convinced immunologists that the immune system had nothing whatsoever to do with cancer. After all, in their hands, it pretty much seemed to ignore tumors.

Thus today’s spectacular results, albeit in a handful of patients, are the result of a rapid pendulum swing from one end to the other, a swing made possible by exponential technological advancements that changed how immune function was perceived. Starting in the 1990s, it became clearer how innate immunity got the ball rolling. Technical improvements made using them to jump-start T cell responses easier. Appreciation of what T cells were capable of expanded. With such data, T cells driven to attack tumor cells was no longer a heretical notion. That was on the T cell side. On the B cell side, César Milstein and Georges J. F. Köhler‘s Nobel worthy technical achievement, the monoclonal antibody, was tailor-made for fighting tumors. Exquisite specificity and sensitivity of antibodies for their targets could be exploited for anything from directly glomming onto tumors and destroying them to helping reverse the brakes tumors place on immune cells. T and B cell attack on tumors thus became feasible. Field’s moved so fast, in <10 years we have >30 companies focused on cancer immunotherapy.

Brings us back full circle to Coley. How did he hit upon the notion that bacterial toxins could be used to cure tumors? No obvious connection between the two. Genesis for Coley’s idea starts at a rather unlikely place. Spontaneous cancer remissions. Rare enough to be well reported in medical literature, since the 18th century, fever and cancer remission were known to be linked. By Coley’s time, such fevers were known to be infectious in origin, specifically bacterial. Reviewing these cases Coley hit upon the idea of using bacterial extracts to induce the same ‘fever’ effect, believing it would yield the same outcome, cancer remission. Modern cancer immunotherapy works to the same end, only it doesn’t mimic an acute bacterial infection but rather recreates its effect, a highly activated immune response. Biggest difference is Coley’s crude extracts could only do much before they ran out of steam while an amped up immune response could be self-sustaining once in the body. Thus the cautionary note is too much collateral damage may dim the promise with inevitable backlash still very much a possibility.

Foot-Note

1. Kienle, Gunver S. “Fever in cancer treatment: Coley’s therapy and epidemiologic observations.” Global advances in Health and Medicine 1.1 (2012): 92-100. http://www.cognition-based-medic…

https://www.quora.com/What-are-the-most-exciting-developments-in-the-field-of-immunology/answer/Tirumalai-Kamala

What are some of the biggest misconceptions about immunology?

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Kevin J. Tracey, noradrenaline, Vagus nerve

Probably the biggest misconception about immunology is that it can be fully understood by studying it in isolation. Preventing us from fully understanding basic physiology, silos dominate our current approach and we study systems separately. Only when endocrinologists, neurologists and immunologists working together becomes the norm can we hope to fully understand how basic physiology differs between health and disease, and only then will our medicine be truly curative.

Research since the 1960s has yielded tremendous mechanistic insight into the major players of the adaptive immune system, the T and B cells, their rules of development and activation, since the 1990s, into the innate immune system and how it underpins the adaptive and so on but as to how the system works within the body, with the neuro and endocrine systems in particular, that’s still largely a mystery because of our siloed approach.

Consider nutrition advice for example. Any given day, we likely see an ad or two on TV exhorting tremendous health and immune function benefits from taking some type of supplement or eating some kind of food. These claims are hardly ever backed by rigorous, reproducible science. We know so by the repeated publication of contradictory observational, correlational studies. Does Vitamin E lower or increase prostate cancer risk? Replace intervention and condition with those from a random news headline of the past few years and same could be said for any number of interventions and conditions. Does blank lower or increase blank risk? Likely beneficial in some, apparently neutral or even harmful in others. We’re no further in our understanding. How do we figure out and predict exactly in whom an intervention is likely to be effective? We don’t have a clue and yet we’ve all heard about the Placebo effect (1). Placebos induce real physiological responses such as changes in blood pressure, brain activity and heart rate, and produce curative effects in conditions ranging from anxiety, depression, pain, even Parkinson’s. In other words, where brain involvement is unmistakably clear. But that’s not all, since innovators outside the mainstream can now show its effects even in conditions such as psoriasis (2).

The placebo effect can only be understood from studying the overlap of immune function with neuro and endocrine, an overlap that’s part and parcel of nature. How do stress hormones like noradrenaline influence immune function (2), how does sleeping after vaccination boost immunological memory (3), how does meditation improve antibody response to influenza vaccine (4), the questions are endless.

Every 10 years or so, a spectacular result from studying them together will make it to the front pages of mainstream, prestigious science, there’ll be a buzz and then it dies down unable to sustain the momentum as the silos continue on largely undisturbed. One famous example to make the point. In 2000, Kevin J. Tracey showed that simply stimulating the Vagus nerve could prevent rats from going into septic shock after they’d been injected with lethal endotoxin designed to do just that (5). Stimulate the parasympathetic pathway (vagus) this way and you can even prevent what should be irreversible trajectory to death. Isn’t that goose-bump worthy remarkable? As well, a profound insight into disease itself. More often than not, the enemy’s within, in the form of unrestrained, fulminant over-reaction. How to guide our responses so they’re more precise and better controlled? Tracey’s results hint at one of the paths ahead. >15 years later, shouldn’t we be closer to have this result be practicably useful for the thousands who die every year from septic shock? Not even close. Of course, being a big name, Tracey’s an exception in sustaining his remarkable streak of innovative, interdisciplinary discovery but the rank and file of endocrinologists, neurologists and immunologists continue mining their silos. To paraphrase Reagan, ‘Tear down those walls already!‘.

Of course, the placebo effect is ruinous for medicine and pharma. It ruins the smooth trajectory of drug development pipeline, weakens effect of promising drugs, and is perceived an overall nuisance. Only if we stick to the orthodoxy though. How about we flip the proposition on its head and instead see the placebo effect as a net opportunity? If we took the effort to scientifically decipher the placebo effect, we’d know when just a sugar pill could do the trick. Heal thyself indeed! Cost savings aside, so many of us would be saved as well from toxic side-effects that are part and parcel of so many drugs. Scientific understanding of the placebo effect could potentially revolutionize medicine, make it much more effective, less costly, safer and more precise. In fact promise of so-called precision medicine is never likely to be fulfilled unless and until we understand how placebos work. Were I a multi-billionaire looking to fund a pet project likely to leave an immeasuarble lasting legacy, I’d do what NIH and other funding agencies currently don’t do, and figure out a way to sustainably fund an interdisciplinary research ecosystem to understand the placebo effect. All of humanity, not just some group here or there, would benefit.

Bibliography:

1. The Placebo Phenomenon. An Ingenious Researcher Finds The Real Ingredients Of ‘Fake’ Medicine. Cara Feinberg, Harvard Magazine, Jan-Feb, 2013.  The Placebo Phenomenon

2. You Can Train Your Body Into Thinking It’s Had Medicine. Jo Marchant, Mosaic Science, 9 Feb, 2016. You can train your body into thinking it’s had medicine

3. Lange, Tanja, et al. “Sleep after vaccination boosts immunological memory.” The Journal of Immunology 187.1 (2011): 283-290. Sleep after Vaccination Boosts Immunological Memory

4. Davidson, Richard J., et al. “Alterations in brain and immune function produced by mindfulness meditation.” Psychosomatic medicine 65.4 (2003): 564-570. http://gruberpeplab.com/teaching…

5. Borovikova, Lyudmila V., et al. “Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.” Nature 405.6785 (2000): 458-462. http://projects.mindtel.com/vade…

https://www.quora.com/What-are-some-of-the-biggest-misconceptions-about-immunology/answer/Tirumalai-Kamala

Why there is no immune response against sperm in female body?

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Anti-sperm antibodies, Ashley Moffett, B. Anne Croy, Regulatory T cell (Tregs), Sarah Robertson

On the contrary, anti-sperm immune response is part and parcel of coitus. Since reproductive immunology is just not part of the mainstream, its practitioners occupy a fringe space within the field, publishing in their own niche journals like Journal of Reproductive Immunology, American Journal of Reproductive Immunology or Placenta, etc. It’s not surprising then that findings that convulse this sub-field and turn long-held notions upside down are simply not well-known outside the niche. Such is the case with anti-sperm immune responses.

In my analysis, three women scientists, Sarah Robertson, Ashley Moffett and B. Anne Croy, have revolutionized reproductive immunology over the last few decades, upending long-held dogmas that never really fit with actual data anyway. Sarah Robertson is at the Robinson Research Institute, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, Australia.

Robertson and others showed that post-intercourse anti-seminal fluid immune response is a normal part of female reproductive tract physiology. This would be jarring only if we considered immune response synonymous with inflammation and in turn inflammation synonymous with damage. That’s far from the truth. Normal post-intercourse anti-seminal fluid immune response consists largely of immune cells with regulatory function. As such they damage neither sperm, seminal fluid nor the female reproductive tract. In fact, Robertson even proposes that proper ‘priming’ of female anti-seminal fluid immune response is important for a healthy pregnancy (1).

Rather than presence/absence of anti-seminal fluid/sperm immune response, type of immune response distinguishes a healthy from an unhealthy female reproductive tract. Seminal fluid itself helps shape regulatory type responses against itself. Not just in humans but also in rodents and livestock, seminal fluid is one of the body’s richest sources of TGF-beta (Transforming Growth Factor-beta; TGF-b1, -b2, -b3) and prostaglandins (2, 3). This suggests they are evolutionarily highly conserved features of seminal fluid in general. In turn, such molecules are essential for conditioning T cells to differentiate towards regulatory function (Regulatory T cell, Tregs). We can also construe presence of such cells in female reproductive tract is important by the fact that women with recurrent miscarriages have far fewer anti-sperm Tregs (4).

Bibliography

1. Robertson, Sarah A., John J. Bromfield, and Kelton P. Tremellen. “Seminal ‘priming’ for protection from pre-eclampsia—a unifying hypothesis.” Journal of reproductive immunology 59.2 (2003): 253-265. http://www.hawaii.edu/behavior/3…

2. Kelly, R. W., and H. O. Critchley. “Immunomodulation by human seminal plasma: a benefit for spermatozoon and pathogen?.” Human Reproduction 12.10 (1997): 2200-2207.

3. Robertson, Sarah A., et al. “Transforming growth factor β—a mediator of immune deviation in seminal plasma.” Journal of reproductive immunology 57.1 (2002): 109-128.

4. Liu, Chaodong, Xian-Zhong Wang, and Xin-Bo Sun. “Assessment of sperm antigen specific T regulatory cells in women with recurrent miscarriage.” Early human development 89.2 (2013): 95-100.

https://www.quora.com/Why-there-is-no-immune-response-against-sperm-in-female-body/answer/Tirumalai-Kamala

Once a killer T-cell has bound on to a virus infected cell and signaled it to apoptose can it re-attach to a new virus infected cell or is it used up?

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CTL (Cytotoxic T Lymphocyte), Gideon Berke, Reinhold Forster, Two-photon excitation microscopy

Many in vitro studies say yes. Back in the 1980s, Gideon Berke was one of the first to use video to track CTL (cytotoxic killer cells) killing target cells. He estimated one CTL was capable of killing 30 to 50 target cells serially. Since then, most studies use the same playbook, namely, in vitro suspension or cell pellet cultures of CTLs with their target cells. Such studies confirmed CTLs

• Can kill multiple targets within a few minutes.
• Can do this both serially as well as simultaneously.

Turns out CTL target killing capacity in vitro is higher than that in vivo. A Feb 2016 issue of Immunity has a paper from Reinhold Forster‘s lab where they used Two-photon excitation microscopy of explanted mouse lymph nodes to assess in vivo CTL killing of virus infected cells (In Vivo Killing Capacity of Cytotoxic T Cells Is Limited and Involves Dynamic Interactions and T Cell Cooperativity. Halle, S. et al. Immunity 44, 1–13, February 16, 2016. http://www.sciencedirect.com/sci…). This study finds

• in vivo CTL target cell killing is much less efficient, killing an average of 2 to 16 virus-infected cells per day.
• CTLs in vivo appear to cooperate with each other in killing their targets (see figure below).

Makes sense because in vivo CTLs have to navigate the complex topography of extracellular matrix and non-target cells in order to find their targets, engage and kill. However, need other studies to confirm these findings to be sure these are consistent features of CTL killing target cells in vivo.

Further reading:

Garcia, Victor, et al. “Estimating the in vivo killing efficacy of cytotoxic T lymphocytes across different Peptide-MHC complex densities.” PLoS Comput Biol 11.5 (2015): e1004178. http://www.ploscompbiol.org/arti…

Elemans, Marjet, et al. “Rates of CTL killing in persistent viral infection in vivo.” PLoS Comput Biol 10.4 (2014): e1003534. http://www.ploscompbiol.org/arti…

Elemans, Marjet, Nafisa-Katrin Seich Al Basatena, and Becca Asquith. “The efficiency of the human CD8+ T cell response: how should we quantify it, what determines it, and does it matter?.” PLOS Comput Biol 8.2 (2012): e1002381. http://www.ploscompbiol.org/arti…

Wiedemann, Aurelie, et al. “Cytotoxic T lymphocytes kill multiple targets simultaneously via spatiotemporal uncoupling of lytic and stimulatory synapses.” Proceedings of the National Academy of Sciences 103.29 (2006): 10985-10990. http://www.pnas.org/content/103/…

Stinchcombe, Jane C., et al. “The immunological synapse of CTL contains a secretory domain and membrane bridges.” Immunity 15.5 (2001): 751-761. http://ac.els-cdn.com/S107476130…

https://www.quora.com/Once-a-killer-T-cell-has-bound-on-to-a-virus-infected-cell-and-signaled-it-to-apoptose-can-it-re-attach-to-a-new-virus-infected-cell-or-is-it-used-up/answer/Tirumalai-Kamala