What is the Missing Self hypothesis of organ transplant rejection?

Tags

Missing Self Hypothesis, NK cell, Transplant, Transplantation

What is the Missing Self Hypothesis?

MHC class I molecules (Human MHC is called HLA) are typically expressed on the cell surface by all body cells save some specific cell types such as sperm and eggs. In the 1980s, the Swedish immunologist Klas Kärre – Wikipedia noticed reduced (down-regulation) cell-surface MHC class I expression was fairly common following viral infections, cancerous transformation and other types of cellular stress, and that precisely such lack of surface MHC class I seemed to make such cells a target for cytotoxic killing by NK cells (Natural killer cell – Wikipedia). Karre postulated that some then as-yet unknown NK receptors were scanning cell surfaces for presence or absence of MHC class I molecules, getting activated and killing those that lacked cell-surface MHC class I, i.e., Missing Self (1, 2). This is a very different process from how cytotoxic CD8 T cells engage antigen-derived epitopes presented within MHC class I molecules.

Circa 2017, Missing Self is much more complicated, outcome of as-yet incompletely understood interactions of a dizzying array of NK cell activating and inhibitory receptors called KIRs.

Thirty years on, the Missing Self idea is clearly not so simple. NK cells themselves seem far more complex than just innate immune cells with invariable germline-encoded receptors. Instead, parallel to and complementing T and B cells, NK cells seem to have evolved a highly complex and more pertinently, highly specific process for recognizing their target cells (3), a process strikingly different from the one used by T cells, which is of somatically rearranged cell-surface receptors binding MHC-bound peptides on presenting cells.

Rather, NK cells express a wide array of cell surface activating and inhibitory receptors, the KIRs (Killer-cell immunoglobulin-like receptor – Wikipedia), and outcome depends on the balance of what they bind, namely, MHC class I as well as as-yet unknown ligands expressed on target cells (see below from 4).

NK cells appear to get activated when multiple activating KIRs are engaged, which overrides inhibitory KIR binding. There is as yet no consensus of how KIRs help shape NK cell ‘education’ during their development in the bone marrow, especially how they learn self-tolerance, with a variety of models, Arming, Disarming, Confining, (5, 6) emphasizing different aspects of the process while the Rheostat model favored by the Swedish group tries to encompass them (see below from 7).

More recent studies complicate matters further by suggesting NK KIRs are sensitive to peptides presented by the HLA class I molecule (8). Also worth noting that most of these models are based on data generated using circulating (blood) NK cells and who knows whether or how relevant such models are to tissue-resident NK cells such as uterine NK cells, whose proper functioning is known to be critical for healthy pregnancies through NK cell KIR engagement by placental trophoblast HLA-C (9), and where proper uNK cell functioning includes extensive uterine tissue remodeling through cytokine secretion to help it quickly adapt to increased vascular supply for the growing fetus (10).

Could mismatch between NK Cell KIRs and tissue KIR ligands Influence transplant rejection?

Since most transplants are allogeneic, between genetically non-identical individuals (Allotransplantation – Wikipedia), HLA matching is done to reduce scope of T cell-mediated rejection. Do transplants need NK cell KIR and tissue KIR ligand matching as well? Available data is somewhat confusing as would be expected with triggers that activate or inhibit NK cells remaining not fully defined.

Nevertheless, since the early 2000s, a steady drip of scientific articles suggest KIR-KIRL (KIR ligands including HLA) matching could improve long-term kidney transplant survival while more recent studies suggest such matching may matter for other transplants such as liver as well. OTOH, in what surely sounds surprising, KIR-HLA mismatching might also improve graft tolerance by killing donor antigen-presenting cells, which would reduce direct antigen presentation by graft.

Thus, even with HLA compatible transplants, recipient NK cells expressing an inhibitory receptor could be activated by allograft cells that lack the HLA class I ligands relevant for that particular inhibitory receptor (11).

Human kidney transplants in particular suggest NK cell mismatch in terms of NK cell inhibitory KIR receptors and missing HLA class I can adversely affect long-term renal allograft survival.

While at least one study (12) that retrospectively analyzed KIR ligand mismatches in 608 cadaveric kidney grafts didn’t find significant differences in 10-year graft survival rates, many other studies (13, 14, 15, 16, 17, 18) support the idea that KIR matching in addition to HLA matching would improve long-term renal graft survival.

One study found KIR-KIRL matching to affect liver rejection rates with higher acute rejection for mismatches (19).

Finally, it’s also worth remembering that NK cells could also be activated to damage allografts through ADCC (Antibody-dependent cell-mediated cytotoxicity – Wikipedia), a process dependent on their antibody-binding Fc receptor – Wikipedia, not on KIRs (4).

Bibliography

1. Kärre, Klas, et al. “Selective rejection of H–2-deficient lymphoma variants suggests alternative immune defence strategy.” Nature 319.6055 (1986): 675-678. https://www.researchgate.net/pro…

2. Ljunggren, Hans-Gustaf, and Klas Kärre. “In search of the ‘missing self’: MHC molecules and NK cell recognition.” Immunology today 11 (1990): 237-244.

3. Yawata, Makoto, et al. “MHC class I–specific inhibitory receptors and their ligands structure diverse human NK-cell repertoires toward a balance of missing self-response.” Blood 112.6 (2008): 2369-2380. http://www.bloodjournal.org/cont…

4. Rajalingam, Raja. “The impact of HLA class I-specific killer cell immunoglobulin-like receptors on antibody-dependent natural killer cell-mediated cytotoxicity and organ allograft rejection.” Frontiers in immunology 7 (2016). https://www.ncbi.nlm.nih.gov/pmc…

5. Höglund, Petter, and Petter Brodin. “Current perspectives of natural killer cell education by MHC class I molecules.” Nature reviews. Immunology 10.10 (2010): 724.

6. He, Yuke, and Zhigang Tian. “NK cell education via nonclassical MHC and non-MHC ligands.” Cellular and Molecular Immunology 14.4 (2017): 321. https://www.ncbi.nlm.nih.gov/pmc…

7. Kadri, Nadir, et al. “Dynamic regulation of NK cell responsiveness.” Natural Killer Cells. Springer International Publishing, 2015. 95-114. https://www.researchgate.net/pro…

8. Carrillo-Bustamante, Paola, Rob J. de Boer, and Can Keşmir. “Specificity of inhibitory KIRs enables NK cells to detect changes in an altered peptide environment.” Immunogenetics (2017): 1-11. https://link.springer.com/conten…

9. Hiby, Susan E., et al. “Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success.” Journal of Experimental Medicine 200.8 (2004): 957-965. http://jem.rupress.org/content/j…

10. Rätsep, Matthew T., et al. “Uterine natural killer cells: supervisors of vasculature construction in early decidua basalis.” Reproduction 149.2 (2015): R91-R102. https://www.researchgate.net/pro…

11. Rajalingam, Raja. “Variable interactions of recipient killer cell immunoglobulin-like receptors with self and allogenic human leukocyte antigen class I ligands may influence the outcome of solid organ transplants.” Current opinion in organ transplantation 13.4 (2008): 430-437.

12. Tran, T. H., et al. “No Impact of KIR‐Ligand Mismatch on Allograft Outcome in HLA‐Compatible Kidney Transplantation.” American Journal of Transplantation 13.4 (2013): 1063-1068. No Impact of KIR‐Ligand Mismatch on Allograft Outcome in HLA‐Compatible Kidney Transplantation

13. van Bergen, Jeroen, et al. “KIR‐ligand mismatches are associated with reduced long‐term graft survival in HLA‐compatible kidney transplantation.” American Journal of Transplantation 11.9 (2011): 1959-1964.; http://onlinelibrary.wiley.com/d…

14. Rajalingam, R., and H. M. Gebel. “KIR‐HLA Mismatching in Human Renal Allograft Transplantation: Emergence of a New Concept.” American Journal of Transplantation 11.9 (2011): 1771-1772. http://onlinelibrary.wiley.com/d…

15. Kunert, Kristina, et al. “KIR/HLA ligand incompatibility in kidney transplantation.” Transplantation 84.11 (2007): 1527-1533. KIR/HLA Ligand Incompatibility in Kidney Transplantation : Transplantation

16. Vampa, Maria Luisa, et al. “Natural killer-cell activity after human renal transplantation in relation to killer immunoglobulin-like receptors and human leukocyte antigen mismatch1.” Transplantation 76.8 (2003): 1220-1228. Natural killer-cell activity after human renal… : Transplantation

17. Nowak, Izabela, et al. “Killer immunoglobulin-like receptor (KIR) and HLA genotypes affect the outcome of allogeneic kidney transplantation.” PloS one 7.9 (2012): e44718. http://journals.plos.org/plosone…

18. Littera, Roberto, et al. “KIR and their HLA Class I ligands: Two more pieces towards completing the puzzle of chronic rejection and graft loss in kidney transplantation.” PloS one 12.7 (2017): e0180831. http://journals.plos.org/plosone…

19. Legaz, Isabel, et al. “KIR gene mismatching and KIR/C ligands in liver transplantation: consequences for short-term liver allograft injury.” Transplantation 95.8 (2013): 1037-1044. https://www.researchgate.net/pro…

https://www.quora.com/What-is-the-Missing-Self-hypothesis-of-organ-transplant-rejection/answer/Tirumalai-Kamala

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Does processed milk cause multiple sclerosis flare up?

Tags

Butyrophilin, EBV (Epstein-Barr virus), Milk, Molecular mimicry

Brief History Of Nebulous Connection Between Milk & MS (Multiple Sclerosis)

Sparse data on this subject consists of

• An US epidemiological study that compared 1949 to 1967 MS mortality rates and food consumption data, and found high correlation (0.8 to 0.9) with milk consumption (1).
• A couple of cross-sectional epidemiological studies from 1976 (2) and 1992 (3) that compared MS prevalence and dairy product consumption. The second one looked across 29 populations in 27 countries and suggested MS progression could be influenced by factors in liquid cow’s milk but not in processed milk.

The story then appeared to lie dormant for the next several years until revived by a 2000 rat EAE (Experimental autoimmune encephalomyelitis – Wikipedia) model study (4). This study mechanistically showed Butyrophilin – Wikipedia, a milk fat globule membrane protein expressed only by the lactating mammary gland,

• Could stimulate MOG (Myelin oligodendrocyte glycoprotein – Wikipedia) -specific T cell – Wikipedia in vitro. MOG is a purported target of immune attack in MS.
• Induce EAE in Dark Agouti and Brown Norway rats.
• Block MOG-induced EAE in Dark Agouti rats.

Similar experiments in a mouse model (5) also showed Butyrophilin could prevent MOG-induced EAE, i.e., that this milk component could protect against EAE.

Problem is though originally developed in the 1950s to supposedly mimic human MS, these rodent (mainly rat and mouse) models simply don’t mimic human MS very well (6), haven’t yielded much insight or practical therapies and yet have taken over basic MS research and remain the mainstay in the field.

Meantime, a couple of small human studies from France (n=44 MS versus 30 controls, 7) and the US (n= 35 MS versus 25 controls, 8) yielded contradictory data

• The French study (7) found MS patients with higher circulating antibody levels cross-reactive to MOG and Butyrophilin.
• The US study (8) found MS patients and controls had similar levels of circulating antibodies cross-reactive to MOG and Butyrophilin. However, this US study also compared anti-MOG and -Butyrophilin antibody responses in blood as well as CSF (Cerebrospinal fluid – Wikipedia) of MS patients and found they were specific for different epitopes (parts) of Butyrophilin, the one dominating in the CSF also cross-reacting to a homologous MOG peptide in 34% of MS patients, i.e., possible Molecular mimicry – Wikipedia between MOG and Butyrophilin.

In addition to these two human studies contradicting each other, these purely observational studies examined circulating antibody levels, i.e., B cell – Wikipedia, not T, cell response as the animal model studies did. Apples and oranges.

While Butyrophilin’s plausible role in MS progression lies in its high sequence similarity to MOG (9), i.e., Molecular mimicry – Wikipedia, data from these two small human studies are inconclusive and so far there’s no other data on milk proteins’ role in MS prognosis or disease course (10).

How Milk Or Any Other Factor Might Trigger Or Flare MS (Multiple Sclerosis)

Though there are many suspects, confirmed triggers for MS are still unknown. Most convincing data exist not for dietary factors such as milk but for vitamin D levels and its receptor polymorphisms, history of Epstein-Barr virus infection including Infectious mononucleosis – Wikipedia and smoking (11, 12).

No matter the trigger though, how might MS disease cascade follow? Prime suspect is molecular mimicry, i.e., molecular level similarity between such triggers and the target of autoimmune attack in MS, typically proteins such as MOG expressed on Oligodendrocyte – Wikipedia, myelin sheath cells.

• However, even this is insufficient. Consider milk for example. Many more people drink milk than get MS. If molecular mimicry alone sufficed, they should all have MS and they don’t.
• Clearly other factors are also involved. No matter the degree of molecular mimicry, nothing can ensue if a person’s immune system can’t ‘see’ it.
  • An immunologically necessary condition would thus be the HLA (Human leukocyte antigen – Wikipedia) haplotype. However, HLA haplotype alone wouldn’t suffice because far more people share HLA haplotypes than develop MS.
  • Breakdown in T cell tolerance is also necessary. After all, during their development in the thymus, T cells with the capacity to recognize oligodendrocyte proteins should get deleted. Obviously that process seems to fall short in MS patients.
• Thus target antigen (and molecular mimic)-specific T cells should be present and such target(s) of immune attack should be properly processed and presented to these T cells. However, though appropriate HLA haplotype and CNS (Central nervous system – Wikipedia) protein(s)-specific T cells are the necessary building blocks for MS autoimmune pathology, their presence alone doesn’t suffice either.
• Context is also necessary, i.e., predisposing and/or conditioning factors necessary to drive the pathological immune response necessary for MS expression. Totality of such factors, sufficient to explain MS in each and every case, still remain undefined.

Bibliography

1. Agranoff, BernardW, and David Goldberg. “Diet and the geographical distribution of multiple sclerosis.” The Lancet 304.7888 (1974): 1061-1066. https://deepblue.lib.umich.edu/b…

2. Butcher, J. “The distribution of multiple sclerosis in relation to the dairy industry and milk consumption.” The New Zealand Medical Journal 83.566 (1976): 427-430)

3. Malosse, D., et al. “Correlation between milk and dairy product consumption and multiple sclerosis prevalence: a worldwide study.” Neuroepidemiology 11.4-6 (1993): 304-312.

4. Stefferl, Andreas, et al. “Butyrophilin, a milk protein, modulates the encephalitogenic T cell response to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis.” The Journal of Immunology 165.5 (2000): 2859-2865. http://www.jimmunol.org/content/…

5. Mañá, Paula, et al. “Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin.” International immunology 16.3 (2004): 489-499. https://www.researchgate.net/pro…

6. Tirumalai Kamala’s answer to Why can chemicals that block the alpha tumour necrosis factor make multiple sclerosis worse? Do inhibiting cytokines make inflammation worse?

7. De March, A. Kennel, et al. “Anti-myelin oligodendrocyte glycoprotein B-cell responses in multiple sclerosis.” Journal of neuroimmunology 135.1 (2003): 117-125.

8. Guggenmos, Johannes, et al. “Antibody cross-reactivity between myelin oligodendrocyte glycoprotein and the milk protein butyrophilin in multiple sclerosis.” The Journal of Immunology 172.1 (2004): 661-668. http://www.jimmunol.org/content/…

9. Vojdani, Aristo. “Molecular mimicry as a mechanism for food immune reactivities and autoimmunity.” Altern Ther Health Med 21.Suppl 1 (2015): 34-45. http://bant.org.uk/wp-content/up…

10. Von Geldern, Gloria, and Ellen M. Mowry. “The influence of nutritional factors on the prognosis of multiple sclerosis.” Nature Reviews Neurology 8.12 (2012): 678-689.

11. Belbasis, Lazaros, et al. “Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses.” The Lancet Neurology 14.3 (2015): 263-273.

12. Tirumalai Kamala’s answer to Why does Colorado have the highest rate of multiple sclerosis?

https://www.quora.com/Does-processed-milk-cause-multiple-sclerosis-flare-up/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

Which Class I MHC alleles have “non-canonical” anchor positions (other than the 2nd and last peptide positions)?

Tags

Anchor residue, H2-D, H2-K, H2-L, HLA-A, HLA-B, HLA-C, HLA-E, HLA-G, Qa-1, Qa-2

Answer by Tirumalai Kamala:

I’ll start with a few definitions to help a general reader.

Definitions
Anchor residues are “conserved positions in a peptide repertoire for a given MHC allele that “anchor” the peptide in the MHC groove” (1).
MHC Isotype: A particular MHC locus. HLA-A, -B, or -C are three classical MHC class I loci.
MHC Allotype: Alleles, i.e., genetically distinguishable forms of the molecule.

MHC class I molecules are classified as classic (for example HLA-A, -B, -C in human) and non-classical (for example HLA-G, -E in human)

Classical MHC class I molecules, HLA-A, B, C (human); H2-K, D, L (mouse)
Classical MHC class I molecules are highly polymorphic, which enables them to bind and present a wide variety of peptides to the ab receptor of T cells, preferentially CD8+ T cells. Most MHC class I molecules bind octamers (peptides that are 8 amino acids in length) or nonamers (9 amino acid length peptide). Each MHC molecule is theoretically capable of binding thousands of different peptides. How could it do that? Each MHC molecule has a peptide-binding groove. Peptides get bound in this groove like a hot dog in a hot dog bun. Can any random peptide bind an MHC peptide binding groove? No, certain positions in an MHC molecule’s peptide binding groove are very restricted in the choice of amino acids they bind. They are called anchor positions, and they ensure that out of the thousands of peptides available from intra-cellular protein degradation and digestion, only specific sequences get bound and presented by a specific MHC class I allele. In 1991, Falk et al defined an anchor position as one “occupied by a fixed residue or by one of a few residues with closely related side chains” (2). Their study found anchor positions at 5 and 9 for H2-Db, 2 and 9 for H2-Kd, and 5 and 8 for H2-Kb, H2-Db, H2-Kd and H2-Kb being mouse classical MHC class I molecules. In humans, HLA-A*02:01 represents the canonical archetype with anchor positions at 2 (Leucine and Methionine preferred) and 9 (Valine, Leucine, Isoleucine and Methionine preferred).

So, which class I MHC molecules anchor peptides at positions other than 2 and the last?

This table is from the online resource, Statistics. 9, 437 alleles? That’s a lot!

I suggest to browse through this handy online resource to find those that anchor at  positions other than 2 and the last. Take HLA-B*08:01 for example, which anchors at 5 and 9.

From the online resource, MHC Class I Allele B restricted epitopes

You can browse by allele here: Browse By MHC Allele

As you browse through, you will also find that anchor positions have not yet been mapped for many MHC alleles.

The picture is different with HLA-C, -E, and -G. HLA-C is the most recently evolved classical HLA class I isotype (3, 4), being present only in hominids. When Rasmussen et al (5) did a detailed analysis of peptide-binding specificity of HLA-C allotypes in 2014 (5), they found “HLA-C*14:02 has a very unusual and promiscuous binding motif with no clear P2 or P3 anchor residues and only a weak P9 primary anchor”.

From 5
Thus,  HLA-C*14:02 is a newly discovered example of a classical MHC class I molecule with non-canonical anchor positions.

Non-classical MHC class I molecules. HLA-E, -G in human; Qa-1, and -2 in mouse
HLA-E (human)
The fun thing about HLA-E is what it presents, peptides derived from leader sequences of other MHC class I molecules! Signal peptidases cut the signal sequence of classical MHC molecules, and their hydrophilic N-terminus portions are released into the cytosol where they are processed by the proteasome, resulting in a leader peptide (6), which binds the peptide-binding groove of HLA-E.
Unlike classical MHC class I molecules, HLA-E has 5 anchor positions, at 2, 3, 6, 7 and 9 (1, 7, 8, 9, 10).

From 11

HLA-G (human)
HLA-G is very restricted in expression, being largely confined in humans to fetal extravillous trophoblasts in the placenta. While HLA-G has a more promiscuous peptide-binding capacity compared to HLA-E, its peptide repertoire is much more restricted because of its placenta-specific expression.
HLA-G has 3 anchor positions, at 3, 4, 9 (1).

Qa-1 (mouse)
Like HLA-E, Qa-1 preferentially presents leader sequence peptides derived from other MHC class I molecules, and also has the same 5 anchor positions, at 2, 3, 6, 7 and 9 (1).

From 11

Qa-2 (mouse)
Qa-2 is the functional homolog of HLA-G (1) and has 3 anchor positions, at 2, 3, 9.

Bibliography

1. Adams, Erin J., and Adrienne M. Luoma. “The adaptable major histocompatibility complex (MHC) fold: structure and function of nonclassical and MHC class I-like molecules.” Annual review of immunology 31 (2013): 529-561
2. Page on uiowa.edu
3. Page on nih.gov
4. Chimpanzees Use More Varied Receptors and Ligands Than Humans for Inhibitory Killer Cell Ig-Like Receptor Recognition of the MHC-C1 and MHC-C2 Epitopes
5. A General Strategy To Determine the Specificity of Any MHC Class I Molecule
6. Page on intechopen.com
7. Page on els-cdn.com
8. HLA-E Allelic Variants
9. Hoare HL, Sullivan LC, Pietra G, Clements CS, Lee EJ, Ely LK, et al. Structural basis for a major histocompatibility complex class Ib-restricted T cell response. Nat Immunol 2006;7:256.
10. Page on nih.gov
11. A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

Which Class I MHC alleles have “non-canonical” anchor positions (other than the 2nd and last peptide positions)?