Rag deletion in peripheral T cells prevents TCR revision (82.10)

Abstract

Abstract In Vβ5 TCR transgenic (Tg) mice, CD4+Vβ5+ T cells are reactive to a peripherally expressed endogenous superantigen. Most self-reactive CD4+ T cells are deleted in the periphery, but through the process of TCR revision, some lose Vβ5 surface expression, re-express Rag genes, undergo rearrangement of endogenous TCRβ, and express a newly formed TCR. As Vβ5 Tg mice age, TCR revision results in the accumulation of post-revision CD4+TCRβ+Vβ5- cells. We now show that post-revision CD4+ T cells undergo extensive homeostatic proliferation in lymphopenic hosts. MHC drives maximal proliferation. Additionally, post-revision CD4+ T cells in Vβ5 Tg mice generate an antigen-specific IFNγ response to Listeria infection. To further investigate the importance of TCR revision, we devised a strategy for removing the Rag2 gene in peripheral T cells. Mice bearing a floxed Rag2 gene and a Cre transgene driven by the distal lck promoter were crossed to ROSA26 YFP reporter mice, in which YFP reports Cre activity. Adoptive transfer of sorted Vβ5+YFP+ T cells from control Rag+/+ mice results in the generation of post-revision T cells, while Vβ5+YFP+ T cells from Ragfl/fl mice remain Vβ5+. Our results illustrate that TCR revision contributes to the ongoing immunocompetence of Vβ5 Tg mice, and that Rag expression in peripheral T cells is necessary for the generation of Vβ5-CD4+ T cells in Vβ5 Tg mice. This work was funded by NIH RO1 Grant #AG13078.