Identification of an Essential IL15-STAT1-IRX3 Prosurvival Pathway in T Lymphocytes with Therapeutic Implications

Abstract

IRX3 homeobox transcription factor plays a role in neural development and in the pathogenesis of obesity and insulin resistance. T lymphocytes play an essential role in the pathogenesis of obesity and their expansion and differentiation is a tightly controlled process. Circulating cytokines trough activation of cell death mechanisms controls the number of CD4 and CD8 T cells, and failure to activate apoptosis is considered the main cause for their uncontrolled expansion. Here, the identification an essential anti-apoptotic pathway in T lymphocytes is presented, whereby IL-15 activation of Stat/Jak signaling cascade leads to induction of the IRX3 expression. IRX3, in turn, promotes T cells survival and self-renewal, at least partially, by controlling the expression of T-bet transcription factor eomesodermin (EOMES). The Stat/Jak signaling inhibition by Jak inhibitor 1 suppresses IRX3 transcription in T lymphocytes and tumor cell lines and increases apoptosis after growth factor deprivation. Our results demonstrate that IRX3 is essential in T lymphocytes differentiation and reveal that the IL-15-dependent IRX3 pro-survival pathway provides potential therapeutic target for regulation of T cell proliferation that has implications for immune cell malignancies, obesity and autoimmune diseases.