The positively selected T cell repertoire: is it exclusively restricted to the selecting MHC?

Transgenic lines of mice showing compartmentalized expression of MHC I-E in different thymic microenvironments and nearly normal expression in the periphery were used to ask whether the mature T cell repertoire is restricted exclusively to the selecting MHC molecules expressed on thymic cortical epithelial cells. We show that upon in vivo priming, mice with a T cell repertoire selected in the thymic cortex on MHC I-A, in the absence of MHC I-E, display a clearly significant T cell response to two I-E-restricted peptides. Our results suggest that expression of one isotype or allele of class II MHC molecules in the appropriate thymic environment enables the selection of a polyclonal repertoire restricted in part to non-selecting class II MHC molecules. Thus, although the requirement for interaction with the MHC by the TCR on developing thymocytes exists, the available adult repertoire need not be solely faithful to the specific MHC expressed on the thymic cortical epithelium: it can also be restricted to other isotypes and alleles of this same class of MHC molecule.