T cells and their eons-old obsession with MHC

Abstract

T cells bearing receptors made up of α and β chains (TCRs) usually react with peptides bound to major histocompatibility complex proteins (MHC). This bias could be imposed by positive selection, the phenomenon that selects thymocytes to mature into T cells only if the TCRs they bear react with low but appreciable affinity with MHC + peptide combinations in the thymus cortex. However, it is also possible that the polypeptides of TCRs themselves do not have random specificities but rather are biased toward reaction with MHC. Evolution would therefore have selected for a collection of TCR variable elements that are prone to react with MHC. If this were to be so, positive selection would act on thymocytes bearing a pre biased collection of TCRs to pick out those that react to some extent, but not too well, with self MHC + self-peptides. A problem with studies of this evolutionary idea is the fact that there are many TCR variable elements and that these differ considerably in the amino acids with which they contact MHC. However, recent experiments by our group and others suggest that one group of TCR variable elements, those related to the mouse Vβ8 family, has amino acids in their CDR2 regions that consistently bind a particular site on an MHC α-helix. Other groups of variable elements may use different patterns of amino acids to achieve the same goal. Mutation of these amino acids reduces the ability of T cells and thymocytes to react with MHC. These amino acids are present in the variable regions of distantly related species such as sharks and human. Overall the data indicate that TCR elements have indeed been selected by evolution to react with MHC proteins. Many mysteries about TCRs remain to be solved, including the nature of auto-recognition, the basis of MHC allele specificity, and the very nature and complexity of TCRs on mature T cells.

Fig. 1. Structure of a TCR + MHC + peptide complex

Shown is the X-ray crystallographically solved structure of the YAe62.8 TCR bound to IA^b + the 3K peptide (33). The TCR V region loops (CDR1-3) of each of the TCR chains are highlighted in color.

Fig. 2. Amino acid sequences of the CDR2β regions of mouse Vβs illustrate residues shared between different Vβs

The amino acid sequences of the CDR2 regions of mouse Vβs are shown. (A) The Y46 Y48 tyrosine motif shared by relatives of the mouse Vβ8 family are highlighted in red. The acidic amino acids that often form salt bridges with basic amino acids in MHCII are colored green (D or E at position 54) or blue (other D or E in this region). (B) The R S motif that makes contact with MHC in two structures containing Vβ2 is colored red (39).

Fig. 3. In different TCR + MHC + peptide complexes, Y48 of TCR Vβs that include it binds to the same site on MHCII but is more variably positioned on MHCI

The positions of TCRβ Y48 in (A) 6 MHCII engaged structures and (B) 4 MHCI engaged structures is shown, with the tyrosine colored in cyan.

Fig. 4. TCRβ Y46 and Y438 adopt similar positions and configurations when engaging MHCII or MHCI

The YAe62 TCR can bind MHCII + the 3K peptide and MHCI + a different peptide. Shown are the positions of TCRβ Y46 and Y48 when bound to (A) IA^b + 3K or (B) K^b + a different peptide. These data were previously shown in a different figure in Yin et al. (42).

Fig. 5. Replacement of TCRβ Y48 with an alanine in mice expressing a Vβ8-containing TCRβ as their only TCRβ chain severely reduces positive selection of T cells

A TCRβ chain containing the WT DO11.10 TCRβ chain or the same chain with Y46 or Y48 replaced by alanines (Y46A or Y48A) was introduced into C57BL/6 embryos. The mice so generated were crossed to mice deficient in TCRβ (108) and intercrossed to produce mice that could make only the transgenic TCRβ and any TCRα. Thymi in these mice were analyzed for their content of mature CD4⁺ and CD8⁺ cells. Shown are the means and SEMs of at least three mice of each type.

Fig. 6. Acidic amino acids in CDR2β often make salt bridges with lysines in MHCII

The X-ray crystallographically established positions of acidic amino acids in four TCRs engaged with MHCII + peptide, and their salt bridges with Ks in MHCII are shown. The data shown are from (A) Dai et al. (33), (B) Newell et al. (56), (C) Yin et al. (63), and (D) Hennecke et al. (64, 65).

Fig. 7. Replacement of TCRα Y29 with an alanine in mice expressing a Vα4-containing TCRα as their only TCRα chain reduces positive selection of T cells

Mice were produced as described in Fig. 5 except that they expressed a single TCRα that of B3K508 (109) and any possible TCRβ. Thymi were analyzed for the numbers of CD4⁺ and CD8⁺ T cells they contained. Data shown are the means and SEMs of at least three mice of each type.