Control of TCR V(α)-mediated positive repertoire selection and alloreactivity by differential J(α) usage and CDR3α composition

Abstract

In rats expressing the f allele of the rat MHC (RT1(f)), CD8 T cells utilizing the V(α)8.2 segment are 10-fold overselected during thymic development, resulting in V(α)8.2 expression by 14% of mature CD8 T cells as compared to 1-2% in MHC congenic strains. In the alloreactive response of CD8 T cells from RT1(f)-negative rats against RT1(f), V(α)8.2+ CD8 T cells are also preferentially expanded. Neither overselection nor alloreactivity of V(α)8.2+ TCR require selective Vβ pairing. However, RT1(f) alloreactive V(α)8.2+ TCR preferentially use a related set of J(α) segments which contribute short homogeneous CDR3α loops, with features suggesting peptide promiscuity, and little N additions. In contrast, only few overselected V(α)8.2+ CD8 T cells showed an imprint of positive selection on J usage or CDR3 composition. The results demonstrate that a single V(α) segment can promote both MHC allele-specific positive selection and alloreactivity, and that the latter is more dependent on an additional contribution of CDR3α, possibly by promoting reactivity with a diverse set of MHC-bound peptides or by providing additional MHC contacts.