Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors

Naturally arising CD25(+) CD4(+) regulatory T cells (T-R) play an important role in the prevention of autoimmunity. TCR specificity is thought to play a critical role in T-R development and function, but the repertoire and specificity of T-R TCRs remain largely unknown. We find by sequencing of TRAV14 (Valpha2) TCRalpha chains associated with a transgenic TCRbeta chain that the T-R and CD25(-) CD4(+) TCR repertoires are similarly diverse, yet only partially overlapping. Retroviral expression of TCRalpha genes in TCR transgenic RAG-deficient T cells revealed that a high frequency of TCRs derived from CD25(+) but not CD25(-) CD4(+) T cells confers the ability to rapidly expand upon transfer into a lymphopenic host. Thus, these data show that a large proportion of naturally arising T-R have substantially more efficient interactions with MHC class II bound peptides from the peripheral self than CD25(-) T cells.