Coevolution of TCR-MHC interactions: Conserved MHC tertiary structure is not sufficient for interactions with the TCR

Abstract

The specificity for self-MHC that is necessary for T cell function is a consequence of intrathymic selection during which T cell antigen receptors (TCRs) expressed by immature thymocytes are tested for their affinity for self-peptide:self-MHC. The germ-line-encoded segments of the TCR, however, are believed to have an innate specificity for structural features of MHC molecules. We directly tested this hypothesis by generating a transgenic mouse system in which the protein HLA-DM is expressed at the surface of thymic cortical epithelial cells in the absence of classical MHC molecules. The specialized intracellular function of HLA-DM has removed this MHC class II-like protein from the evolutionary forces that have been hypothesized to shape TCR-MHC interactions. Our study shows that a structural mimic of MHC class II is not sufficient to appropriately interact with the TCRs expressed by developing thymocytes. This result emphasizes the unique complementarity of TCR-MHC interactions that are maintained by the evolutionary pressures dictated by positive selection.T cell receptor ͉ thymocytes ͉ mice ͉ T lymphocytes ͉ thymus D evelopment of thymocytes is a multistep process that shapes the repertoire of mature T cells. Ideally, the mature T cell antigen receptor (TCR) repertoire is depleted of specificities that are overtly self-reactive, but is also diversified enough to mount effective immune responses (1, 2). Selection is based on the interactions of the TCRs expressed by immature CD4 ϩ CD8 ϩ , double-positive (DP) thymocytes with selfpeptide:self-MHC expressed on the surface of thymic stromal cells. Poorly defined criteria determine whether this receptorligand interaction is of sufficient avidity to drive development of DP thymocytes to mature single-positive, MHC class I-or MHC class II-restricted T cells.Unresolved issues regarding the positive selection of T cells include the extent that specific interactions of the TCR with MHC-bound self-peptides rather than interactions with MHC itself shape the mature CD4 ϩ T cell repertoire. This question has been addressed by a number of systems that have not produced concordant results (3-7). Such contradictory data have led to speculation that different TCRs may have different requirements for recognition of MHC-bound self-peptide. The inherent MHC reactivity of the preselection TCR repertoire is a second issue that has not been definitively answered. In other words, it is not clear whether the germ line-encoded regions of the TCR are predisposed toward interactions with MHC, or, alternatively, whether the ability of TCRs expressed by mature T cells to interact with MHC is fully a consequence of positive selection.Mutagenesis studies have suggested that the TCR has a conserved orientation of interaction with MHC molecules, and, therefore, conserved interactions between MHC molecules and TCRs seemed likely. Crystallographic studies of TCRs bound to MHC, however, have not fully confirmed this prediction (7). In retrospect, perhaps this finding is not surprising, consideri...

Fatal autoimmunity in mice reconstituted with human hematopoietic stem cells encoding defective FOXP3

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Unraveling a Hotspot for TCR Recognition on HLA-A2: Evidence Against the Existence of Peptide-independent TCR Binding Determinants

“…In favor of the former, there is strong evidence for the existence of an intrinsic affinity of TCRs for MHC molecules. 9,10 Nonetheless, crystallographic structures of TCRpeptide/MHC complexes have so far identified few conserved interactions between TCRs and the MHC a1 and a2 helices through which an intrinsic affinity could be mediated. 8,11,12 We have been addressing the distinction between TCR recognition of peptide and MHC by examining different receptors that recognize peptides presented by the class I MHC HLA-A*0201 (HLA-A2).…”

Functional Development of the T Cell Receptor for Antigen

“…129 As another test of the germline compatibility of TCRs with MHC, the class II homolog HLA-DM was expressed on the cell surface in MHC-deficient mice, and this could not restore T cell selection. 130 The question remains open, however, whether this failure resulted from the lack of positive evolutionary pressure on the invariant MHC-like features of HLA-DM or the inability of HLA-DM to present a diverse peptide repertoire (just as the monolithic class II pMHC of Ii/H2M-deficient mice failed to select T cells). 125 …”