Human TCR-MHC coevolution after divergence from mice includes increased nontemplate-encoded CDR3 diversity

Abstract

Chen et al. demonstrate that human MHC selects a larger human TCR repertoire than mouse MHC. They show how humans optimized TCR diversity and suggest that CDR3 length adjusts for different V segment–MHC affinity.

Cross-reactive public TCR sequences undergo positive selection in the human thymic repertoire

“…Interestingly, cross-reactive TCRs were frequently reactive to both MHC I and II (41). Furthermore, in mice genetically engineered to express human TCR genes with either a single allele of human MHC II or a single mouse MHC II, a surprisingly high number of CD4 + TCRs was shared between the 2 groups (42). The finding that single MHCs from different species are able to select shared TCRs provides support for our hypothesis about selection of cross-reactive TCRs.…”

“…A report of increased similarity in V and J gene usage of peripheral naive T cells between identical twins compared with non-twins but overall similar V and J usage frequencies for any 2 donors, regardless of relatedness (56), is consistent with a subtler effect of HLA alleles in selecting for certain V and J genes. In a mouse study (42), selection of T cells on a single murine or human MHC II molecule resulted in some differences in V and J gene usage. However, the proportion of SP thymocytes in these mice was significantly lower compared with that in normal B6 mice, suggesting inefficient selection on a single MHC allele, which could potentially skew the repertoire toward using certain V and J genes.…”

The human fetal thymus generates invariant effector γδ T cells

“…In adults, the γδ TCR repertoire in the peripheral blood becomes less diverse and highly focused, highlighting the potential adaptive function of human γδ T cells (Ravens et al, 2017; Davey et al, 2017; Silva-Santos and Strid, 2017). Thus, it is not clear whether thymic programming of γδ T cells exists in humans, further contributing to the notion that mouse and human γδ T cells are different (Mestas and Hughes, 2004; Pang et al, 2012; Van de Walle et al, 2009), possibly because human TCRs have an inherent bias to N-containing CDR3 regions (Chen et al, 2017).…”

Effective NY-ESO-1–specific MHC II–restricted T cell receptors from antigen-negative hosts enhance tumor regression

“…For this purpose, we employed ABabDR4 mice, which were generated to rearrange human TCRs with HLA-DR4 restriction and do not express the human tumor antigen NY-ESO-1. ABabDR4 mice were shown to express a diverse CD4 + T cell repertoire and are thus a useful model for raising human TCRs in a nonhuman and therefore nontolerant host (19).…”

“…Similarly, CD4 + T cells responded specifically to NY-ESO-1 116 ( Figure 1A). DRB1*0401-IE-transgenic (ABabDR4) mice (4,19,20). The advantage of this model is that CD4 + T cells in ABabDR4 mice bear a diverse human HLA-DRA/DRB1*0401-restricted (HLA-DR4restricted) TCR repertoire but are not influenced by NY-ESO-1specific tolerance, as mice do not express sequences homologous to the HLA-DR4-restricted NY-ESO-1 epitope used in this study.…”