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. T cells bind pMHC (peptides bound to (MHC)). In fact they can bind peptides presented both by MHC expressed by cells in the of the body in which they develop, , as well as by MHC expressed in genetically non-identical transplants, for e.g. during ( ) *. 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(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 ( ).
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. 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 (, , , , , ).
- One suggests the and co-receptors impose it during thymic development. These coreceptors are associated with the unique T cell , and the idea is only those developing T cells, i.e., , 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 ( ), 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,hypothesized ‘parallel evolution’ ( ) of MHC and the then-undiscovered (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 (; see figure below from ).
This 2016 study thus concurs with many previous experimental (mostly mouse and some human) studies that found someamino acid residues on TCR alpha and beta chains to be crucial for binding MHC ( , , , , ).
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 ().
Structural and some functional data from different experimental studies (, , , ) support either model.
One mouse TCR () 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 ( ), i.e., support for the peptide-centric model. Meantime studies with human TCRs and HLA class I ( , ) 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 ofthey’re also obviously unsuitable.
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