A distinct CD38+CD45RA+ population of CD4+, CD8+ and double-negative T cells is controlled by FAS [alps]

The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune-lymphoproliferative syndrome to identify a population of FAS-controlled TCRab+ T cells. They include CD4+, CD8+ and double-negative T cells and can be defined by a CD38+CD45RA+T-BET- expression pattern. These unconventional T cells are present in all healthy individuals, generated before birth, enriched in lymphoid tissue and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T-cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative T cells with IL-10 cytokine bias. Moreover, FCT are as highly glycolytic as EBV-induced effector T cells but their metabolic program is uncoupled from T-bet expression and IFNg production. Mechanistically, regulation of this physiologic population is mediated by FAS and CTLA4 signaling and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease.