Role of purinergic receptor P2X7 in the differentiation and function of iNKT cell subsets

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Metabolic reprogramming supports the differentiation, expansion and functional maturation of effector and memory T cells. It is also contributing to the de-regulation of T cell functions, such as T cell exhaustion in the tumor microenvironment, or break of tolerance in autoimmune diseases. Understanding how distinct metabolic programs are regulated to facilitate lineage specific development and function will provide important insight for designing new therapeutics targeting T cell metabolism. iNKT cells are a group of innate-like T cells, playing important roles in many pathological conditions. iNKT cell differentiation into mature functional subsets NKT1, 2 and 17 in the thymus represents an alternative paradigm of T cell development. In our preliminary study, we have identified distinctive metabolic features of iNKT cell subsets, and the purinergic receptor P2X7 as a new regulator for iNKT cell differentiation. The overall goal of this study is to define the mechanism how P2X7 modulates subset specialization and functional maturation. In Aim 1, we will determine the role of P2X7 as an ATP gated Ca2+ channel to promote optimal Ca2+ signals during iNKT cell differentiation. We will explore the connections between P2X7 and TCR activation, as well as Ca2+ as an important co-factor for mitochondria respiration. In Aim 2, we will define the role of P2X7 as a metabolic regulator during iNKT cell differentiation and activation. We will test if and how P2X7 regulates glucose metabolism, and if the energy sensor AMPK acts down stream of P2X7 activation. The immediate contribution of this study is to reveal novel metabolic components/processes, such as extracellular ATP (eATP, ligands for P2X7), Ca2+ signal, and mitochondria, which can specifically modulate iNKT subsets differentiation and effector functions. The support from a COBRE grant will enable us to take a critical step towards our long-term goal, targeting innate-like T cell metabolism to treat human diseases.