Dissecting the role of CD38 and metabolism in the heightened Treg potential of human neonatal naïve CD4+ T cells

Abstract After birth, the developing human immune system encounters a multitude of new environmental antigens. Balancing protection against infection with immune tolerance to limit detrimental and excessive tissue inflammation is thus a critical function of the neonatal immune system, regulated in part by the capacity of naïve CD4+ T cells to preferentially differentiate into regulatory T cells (Tregs). Immune cell metabolic state is closely tied to function, and emerging research has revealed a distinct metabolic signature for neonatal versus adult CD8+ T cells. Yet, how the metabolic states of early life T cells, particularly CD4+, relate to their distinct functional capacities remains an understudied area of high biomedical relevance to pediatric health and the design of early life therapeutics. I have shown that human neonatal naïve CD4+ T cells preferentially use glycolysis for ATP generation and that this is closely tied to their heightened expression of CD38, a metabolic enzyme with many cellular functions including NAD+ metabolism and intracellular calcium regulation. When treated with a pharmacologic CD38 inhibitor, I observe that neonatal naïve CD4+ T cells demonstrate diminished capacity for Treg differentiation despite preserved cell proliferation and activation. Through the proposed experiments, I aim to test the hypothesis that the distinct metabolic state of human early life naïve CD4+ T cells, driven by their high CD38 expression, facilitates their unique potential for Treg differentiation. To do so, I will define how the metabolic state of neonatal naïve CD4+ T cells impacts their functional potential (Aim 1) and the mechanism by which CD38 shapes the glycolytic dependency and tolerogenic potential of neonatal naïve CD4+ T cells (Aim 2). This work will utilize cutting edge metabolic techniques and immunology assays, as well as pharmacological and genetic approaches, to elucidate the connection between metabolism, CD38, and tolerance in early life. Completion of these aims will shed light on fundamental mechanisms behind a critical time in immune development and build a foundation for precision therapies that aim to augment or limit early life tolerance via modulation of CD38 or other metabolic pathways.