Evolutionarily Conserved Amino Acids That Control TCR-MHC Interaction

Abstract

Alpha/beta T cell receptors (TCRs) react with major histocompatibility complex proteins (MHC) plus peptides, a poorly understood phenomenon, probably because thymocytes bearing TCRs that manifest MHC-reactivity too well are lost by negative selection. Only TCRs with attenuated ability to react with MHC appear on mature T cells. Also, the interaction sites between TCRs and MHC may be inherently flexible and hence difficult to spot. Contacts between TCRs and MHC in the solved structures of their complexes were reevaluated with these points in mind. The results show that frequently used amino acids in TCR CDR1 and CDR2 regions are often used to bind MHC, in areas around small amino acids on the surfaces of MHC α helices that form a cup, allowing somewhat flexible binding of the TCRs. The TCR amino acids involved are specific to families of V regions and partially different rules govern recognition of MHC1 versus MHCII. TermsT cell receptor; MHC; evolution; conserved interactions; tolerance; selection; major histocompatibility complex A HISTORICAL INTRODUCTIONIt is almost 50 years since the discovery that the thymus had something to do with immune responses. Shortly thereafter, cells derived from the thymus were found to improve the ability of B cells to make antibodies, This was followed by the discovery of the carrier effect, i.e. the observation that the antibody response to haptens requires simultaneous recognition of both the hapten and epitopes on the attached protein carrier. These findings dovetailed unexpectedly well to give rise to the idea that T cells created in the thymus react with one portion of the antigen and then help B cells make antibody against a different determinant on the same molecule (1-4). This satisfying explanation for cell cooperation in NIH Public Access Author ManuscriptAnnu Rev Immunol. Author manuscript; available in PMC 2011 September 1.Published in final edited form as: Annu Rev Immunol. 2008 ; 26: 171-203. doi:10.1146/annurev.immunol.26.021607.090421. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptimmune responses left unresolved one key problem for immunologists, the problem of the major histocompatibility complex.The fact that the major histocompatibility complex (MHC) represents a special case for immune responses had been recognized many years before, by people studying the rejection of grafts and tumors (5, 6). They found that differences at the MHC were recognized by the immune system extraordinarily rapidly. This phenomenon led Niels Jerne to propose that lymphocyte receptors, by which, at the time, he meant immunoglobulin proteins, had evolved evolutionary to react with alleles of the MHC (7). In a ground breaking theoretical paper, he suggested that lymphocytes developing in the thymus somatically mutate their evolutionarily generated receptors such that the receptors no longer react with the MHC of their host, but retain the ability to react well with MHC of others.Meanwhile, others were beginning to realize that T and B cells do not re...

Half of the T‐cell repertoire combinatorial diversity is genetically determined in humans and humanized mice

“…Strikingly, the BV5 genes (highly expressed both in humans and humanized mice) present this Y at position 48. Likewise, it has been reported that the BV6 family contacts the MHC molecules in two instances at position 29 of the CDR1 and at position 54 of the CDR2 [33]. Thus, based on these examples, it is tempting to speculate that contacts between evolutionary-conserved residues in the TCR and MHC molecules during thymic positive selection may explain the high proportion of some hTRBV families in the mature T-cell repertoire.…”

“…Indeed, accumulating evidence since the pioneering work of Pannetier et al [31] suggest that there is an inherent bias in the TCR to react with some conserved regions of the MHC molecules, outside of the peptide-binding groove, allowing the 'right' docking of the TCR with MHC molecules for efficient selection [17,32,33]. Recent functional data revealed the important role of Y at position 48 of the hTRBV chain in T-cell positive selection, through contacts with the a domains of both class I and class II MHC molecules [17,34].…”

“…The contribution of endogenous factors to the composition of the hTRBV chain repertoire was proposed to be around 50%, in close agreement with our own estimation based on a totally different set of data and repertoire diversity evaluation technology. Altogether, these results concur with the hypothesis that the underlying rules governing the establishment of the human T-cell repertoire might be less random than previously thought.Indeed, accumulating evidence since the pioneering work of Pannetier et al [31] suggest that there is an inherent bias in the TCR to react with some conserved regions of the MHC molecules, outside of the peptide-binding groove, allowing the 'right' docking of the TCR with MHC molecules for efficient selection [17,32,33]. Recent functional data revealed the important role of Y at position 48 of the hTRBV chain in T-cell positive selection, through contacts with the a domains of both class I and class II MHC molecules [17,34].…”

Identification of Antigenic Determinants, Solvent Accessibility and MHC Binders of Antigen NADH Dehydrogenase Subunit 5 from a Little Dragon from Medina (Dracunculusmedinensis)

“…The involvement of MHC class-I molecule in response to almost all antigens make the study very interesting. They bind to some of the peptide fragments generated after proteolytic cleavage of antigen [27]. Identification of MHC-binding peptides and T-cell epitopes helps improve our understanding of specificity of immune responses [28].…”

Manipulation of MHC-I/TCR Interaction for Immune Therapy

“…Significant changes in TCR CDR3 loops can take place upon binding (57)(58)(59) and CDR3 can occupy different conformations depending upon which ligand is bound (60,61 mechanisms produced occur simul-taneously in the interface, not limited to molecular mimicry and CDR loop shifts (62). Recently, it has been reported that the cross-reactivity correlated with a shrinking, increasingly hydrophobic TCR-ligand interface (63), and a few conserved amino acids in CDR1 and CDR2 were involved in the engagement (63,64).…”