Receptor Revision in Peripheral T Cells Creates a Diverse Vβ Repertoire

Abstract

In Vβ5 transgenic mice, the age-dependent accumulation of Vβ5−CD4+ T cells expressing endogenous Vβ elements represents an exception to the rule of strict allelic exclusion at the TCRβ locus. The appearance of these cells is limited to the lymphoid periphery and is driven by a peripherally expressed tolerogen. Expression of the lymphoid-specific components of the recombinase machinery and the presence of recombination intermediates strongly suggest that TCR revision rescues tolerogen-reactive peripheral T cells from deletion. Here, we report that the appearance of Vβ5−CD4+ T cells is CD28-dependent. In addition, we find that the TCR repertoire of this unusual population of T cells in individual Vβ5 transgenic mice is surprisingly diverse, both at the level of surface protein and at the nucleotide level within a given family of V(D)Jβ rearrangements. This faithful recreation of the nontransgenic repertoire suggests that endogenous Vβ-expressing populations do not arise from expansion of an initially rare subset. Furthermore, the undersized N regions in revised TCR genes distinguish these sequences from those generated in the adult thymus. The diversity of the revised TCRs, the minimal mouse-to-mouse variation in the expressed endogenous Vβ repertoire, the atypical length of junctional sequences, and the CD28 dependence of the accumulation of Vβ5−CD4+ T cells all point to their extrathymic origin. Thus, tolerogen-driven receptor revision in peripheral T cells can expand the TCR repertoire extrathymically, thereby contributing to the flexibility of the immune repertoire.