In the modern framework of immunology, immune receptors are typically classified as either adaptive or innate, the key difference between the two being that innate immune receptors are germline encoded and recognize evolutionarily confined antigens, while adaptive immune receptors are able to recognize rapidly evolving antigens, albeit at the cost of potential autoreactivity. This bifurcation serves well in teaching introductory immunology to students, but fails to represent what is in fact a spectrum of a system. Whether discussing innate receptors recognizing conserved danger-associated molecules, or B cell receptors (BCRs) recognizing unlimited types of antigens, neither description adequately suits T cell receptors (TCRs). The nature of TCRs, in terms of the antigens that they can recognize and their overall role in the immune system, places them somewhere between truly adaptive and innate receptors.

In contrast to innate receptors that are limited to evolutionarily-defined ligands, BCRs (or the analogous variable lymphocyte receptors in lampreys) are theoretically limitless in terms of the antigenic structures that they can recognize. In this respect, antibodies are the epitomic adaptive receptors. TCRs, on the other hand, fall short of that definition due to their restriction by antigen-presenting molecules (APMs). By limiting recognition to antigens presented by APMs, instead of the free antigen, TCRs cannot recognize the range of antigenic structures afforded to antibodies. Haptens are classical examples of this. In fact, APM-restriction is so important that a major fraction of developing thymocytes are disposed for failing to reach the positive selection threshold. Furthermore, the TCR-APM interaction involves innate-like recognition, with evidence supporting germline-encoded residues of TCR V genes mediating interactions with MHC molecules. This is especially the case for some CD1/MR1-restricted TCRs, where specific TCR V genes are employed in the interaction with the monomorphic APM. Therefore, as a result of APM-restriction, TCRs do not possess the same breadth of antigenic repertoire as the definitively adaptive antibodies.

TCR quote

Why is it essential that TCRs are constrained to recognize antigens in the context of APMs? Consider the conventional immune response where innate receptors first activate antigen-presenting cells, which then activate T cells via TCR-APM interactions. T cells provide help to B cells, which express the most adaptive receptor in the immunological arsenal. At each step, one licenses the next for activation. Since the antibody-antigen interaction lacks the evolutionary refinement of innate receptor-DAMP interactions, an antibody is ignorant as to whether its cognate antigen is actually dangerous and therefore warranting of an immune response. It must obtain this information from other signals. By effectively utilizing the APM as a “danger” molecule, TCRs can be more certain that the ligand presented is an antigen of interest, and only with the approval of T cells can the majority of B cells exercise their functions. This idea of adaptive immune regulation is also present with unconventional T-independent antigens, where that signal for B cell activation is instead provided largely by innate receptors. The TCR-APM/antigen interaction serves as another layer of checkpoint in the tightly regulated course of immune response from innate to adaptive, and has been constructed by evolution for this intervening niche.

Through their targeted antigens and niche in the overall immune system, it is clear that TCRs are uniquely positioned between the properties of innate and adaptive immune receptors. While the progression into an adaptive response is unequivocally necessary for host protection, it also becomes progressively more dangerous and less controlled, which necessitates the TCR to minimize the risk of an otherwise unregulated branch of immunity. Thus, because of the restriction imposed onto TCRs, they are entrusted as the crucial gatekeeper between innate and adaptive immune responses.


References:

  1. Lanier, LL. (2013). “Shades of grey – the blurring view of innate and adaptive immunity.” Nature Reviews Immunology. 13:73-74.
  2. Marrack, P et al. (2008). “Evolutionarily conserved amino acids in TCR V regions and MHC control their interaction.” Annual Reviews Immunology. 26:171-203.
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Tim Guo

Tim is currently a PhD candidate in the laboratory of Dr. Naoto Hirano at the Princess Margaret Cancer Centre. The lab and his project explore new ways to engineer T cells for cancer immunotherapy. Outside the lab, he dabbles in the culinary arts and catches up on classic movies.
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