The molecular basis of TCR germline bias for MHC is surprisingly simple

Abstract

The elusive etiology of germline bias of the T cell receptor (TCR) for major histocompatibility complex (MHC) has been clarified by recent ‘proof-of-concept’ structural results demonstrating the conservation of specific TCR-MHC interfacial contacts in complexes bearing common variable segments and MHC allotypes. We suggest that each TCR variable-region gene product engages each type of MHC through a ‘menu’ of structurally coded recognition motifs that have arisen through coevolution. The requirement for MHC-restricted T cell recognition during thymic selection and peripheral surveillance has necessitated the existence of such a coded recognition system. Given these findings, a reconsideration of the TCR–peptide-MHC structural database shows that not only have the answers been there all along but also they were predictable by the first principles of physical chemistry.

A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene

“…This notion contrasts with prevailing dogma, which asserts that germline bias arises as a consequence of allotype-specific MHC reactivity (Garcia et al, 2009). …”

“…Overwhelming experimental data have since accumulated to validate one original proposition that MHC-linked Ir genes dictate the presentation of specific antigens in immunogenic form (Benacerraf and Germain, 1978). There is also some evidence to support the idea that germline-encoded components of the TCR interact preferentially with defined MHC allotypes (Garcia et al, 2009; Scott-Browne et al, 2009), building on the earlier theoretical work of Niels Jerne (Jerne, 1971). However, it has not been shown previously that heritable elements of an antigen receptor can license immune reactivity, a scenario postulated almost four decades ago as an alternative model to explain the Ir gene phenomenon (Benacerraf and Germain, 1978).…”

A Closer Look at TCR Germline Recognition

“…The authors suggest that, by virtue of pairing to an alternative Vα, the TCRβ loop conformations changed and the interaction site of the Vβ domain was significantly modified, leading to an “altered pMHC binding mode” and “modified TCRβ binding reaction with MHC.” They go on to conclude that, consequently, germline specificity, defined as conserved pairwise interactions between Vβ and MHC amino acids, is not consistently observed. Indeed, prior examination of the various complexes between TCRs containing Vβ8.2 and MHC revealed that although Y50 of Vβ8.2 (for example) almost always interacts with MHC, it does not do so in each case with the same atom-to-atom contacts (Garcia et al, 2009; Marrack et al, 2008). As such, the idea that TCR chains, in the course of evolution, have evolved germline residues to interact in a consistent way with MHC molecules appears to have less validity.…”

“…Thus, a given V region may be able to engage different MHC targets in different ways, but using the same V region amino acids (Garcia et al, 2009). This notion is most dramatically illustrated by the interaction of Vβ8.2-bearing TCRs with the nonclassical MHC protein CD1d.…”

Response to Garcia et al.

“…Contacts between these CDR2β and IA b α chain residues occur in the YAe62-IA b -3K structure as well (Dai et al., 2008), which led to a hypothesis for the existence of a conserved, pairwise Vβ8.2-IA interaction motif, termed a “codon” (Feng et al, 2007; Garcia et al, 2009). These CDR2β residues, most notably Y46 and Y48, are also important for thymic selection of T cells carrying the DO TCRβ chain (Scott-Browne et al, 2009).…”