Antioxidation protein Nrf2 modulates glutamine metabolism to regulate activation-driven expansion of CD4 +T-cells

Abstract Nutrient metabolism governs the effector functions like activation, expansion, and subset differentiation of CD4 +T-cells, orchestrators adaptive immunity. The levels reactive oxygen species (ROS), metabolic byproducts cellular are regulated by antioxidation pathway, which is composed Keap1 Nrf2 proteins. We observed that, expression temporally post-activation in +T-cells (high on day 1 low days 2 3) indicating its role +T-cell functions. It yet unknown if how pathway crosstalks with to shape responses. Here, using mice T-cell specific deletion (Keap1-KO) or (Nrf2-KO) we deciphered effects high (antioxidation) levels, respectively +T-cells. Upon activation vitro, Keap1-KO constitutively showed higher proliferation, increased early markers elevated TCR-mediated signaling compared wildtype (WT) cells. In contrast, decreased proliferation lower was noted activated Nrf2-KO To dissect underlying mechanisms, performed metabolite analyses nutrient-limiting conditions. Interestingly, show upregulated glutamine as measured intermediates rely for optimum expansion. Together, our findings identify a mechanism protein metabolically reprograms modulates their dependencies support