A novel mechanism for IL-6 to regulate CD4 cell effector function through mitochondrial respiratory chain. (IRC2P.457)

Abstract

Abstract Mitochondria are the essential engine of the cell to produce energy as ATP through oxidative phosphorylation (OXPHOS). Although less known, mitochondria are also a key regulator of Ca2+ homeostasis both as a major Ca2+ storage as well as a modulator of ER Ca2+. The role of mitochondria metabolism in T cells is a rapidly growing field. It has important impact on activation, differentiation and effector function of CD4 and CD8 cells. STAT3 is a transcription factor that regulates the expression of a number of genes, but it has also been found in mitochondria where it regulates ETC. Since interleukin-6 is one of the major activators of STAT3, we have investigated whether interleukin-6 could regulate mitochondria function. Our studies show that interleukin-6 is essential to maintain mitochondrial hyperpolarization during CD4 T cell activation in a Stat3-dependent manner. Hyperpolarization of mitochondria by interleukin-6 does not affect the production of ATP in CD4 T cells. However, maintaining mitochondrial hyperpolarization by interleukin-6 during activation of CD4 T cells results in increased mitochondrial Ca2+ levels. Consequently, it helps to sustain higher levels of cytosolic calcium. Increased levels of cytosolic Ca2+ facilitate the production of specific cytokines that are regulated by interleukin-6 Thus, we have identified a novel mechanism by which interleukin-6 can play a key role in the function of effector CD4 T cells through its effect on mitochondria.