Junctional diversity prevents negative selection of an antigen-specific T cell repertoire

Abstract

Endogenous mouse mammary tumor proviruses (MMTV; Mtv loci) deletes Vbeta6 expressing T cells in the thymus of Mtv-7(+) DBA/2 (H2(d)) mice through negative selection. We found that in Mtv-7(-) BALB/c (H2(d)) mice, Vbeta6 is a dominant V gene used in T cell responses to an 18 amino acid long peptide antigen: EYKEYAEYAEYAEYAEYA [abbreviated as K5 or EYK(EYA)(5)]. It was therefore surprising to find that despite the deletion of Vbeta6+ T cells, vigorous K5 specific T cell responses that use Vbeta6 can be raised in DBA/2 mice. Sequence analysis of Vbeta6 junctional diversity in K5 specific T cell lines revealed that the DBA/2 K5 repertoire compensates for the loss of most Vbeta6 T cells by overusing and amplifying Vbeta6+ T cells escaping central deletion and peripheral tolerization. In order to address the inability of some Vbeta6 T cells to recognize Mtv-7(+) we analyzed a panel of BALB/c Vbeta6 expressing T cell hybridomas. This data supported the argument that certain Vbeta6 junctional sequences preclude Mtv recognition and allows their escape from central deletion in DBA/2 mice. These cells are not anergic and can be activated with cognate peptide antigen in periphery. We suggest that junctional diversity at the V region of some of the T cell receptors does not allow these cells to recognize self-superantigens with high enough affinity and thus they escape negative selection in the thymus. These results for the first time provide a molecular explanation of how the immune system compensates for "hole in the repertoire" caused by deletion of the majority of T cells carrying certain V region segments.