IFN-gamma Limits Peripheral T cell Expansion of Extrathymic T cells. (89.18)

Abstract

Abstract When overexpressed under the p56Lck proximal promotor, Oncostatin M induces extrathymic T cell development in the lymph nodes. During LCMV infection, extrathymic (ET) T cells produce copious amounts of IFN-γ and their expansion is precocious but of limited amplitude because of early apoptosis. Moreover, ET T cells show significant apoptosis in uninfected mice. Hence, we sought to understand why ET T cells are more susceptible to apoptosis than thymic T cells. We found that the mitochondrial apoptotic pathway is likely involved in apoptosis of CD4+ ET T cells because of lower Il-7Rα and Bcl-2 levels compared to thymic T cells. In contrast, this deficit was not seen in CD8+ ET T cells. However, CD8+ ET T cells displayed higher Fas and active caspase 8 expression indicating apoptosis via the death receptor pathway. Moreover, we found that ET T cells and thymic T cells in homeostatic peripheral expansion (HPE) shared many similarities: memory phenotype, accelerated turnover and increased susceptibility to apoptosis. Moreover, spontaneous IFN-γ secretion by CD8+ ET T cells leading to massive accumulation in sera was observed. Finally, we found that CD8+ T cell survival was restored during HPE induced with ifngR−/−T cells as well as in ifng−/−ET T cells compared to IFN-γ-responsive T cells. Taken together, these results show that IFN-γ regulates apoptosis of ET T cells T cells in HPE and thereby limits their accumulation in vivo.