Suppression of CD4 T cells by Tregs dictates metabolic remodeling of CD8 T cells during effector to memory transition

Metabolic transitions between naïve, effector and memory T cell states are largely orchestrated by TCR, costimulatory and cytokine signals along with nutrient availability in the immune microenvironment. Treg cells have been shown to play a critical role in the effector-to-memory (E-M) transition of virus-specific CD8 T cells through regulation of proliferation and cytotoxic functional programs. However, the precise Treg-dependent metabolic changes that occur in the microniches and, the underlying molecular and cellular mediators of E-M transition remain undefined. Here we show that Treg cells promote the metabolic remodeling of memory-precursor effector CD8 T cells (MPEC) from aerobic glycolysis to fatty acid oxidation as they enter quiescence after antigen clearance. Our data implicate the anatomic microniche of the splenic white pulp as a site for Treg-MPEC interactions. We further show that optimal E-M metabolic transition requires regulation of effector CD4 T cells and inflammatory myeloid cells through inhibitory CTLA4 signals from Treg cells. Moreover, antagonism of inflammatory cytokine interferon-γ (IFN-γ) signals partially rescues the memory defects associated with absence of Treg cells. Together, these findings support a metabolic triad model of memory CD8 T cell differentiation where Treg-dependent regulation of inflammation from effector CD4 T cells promotes the transition of CD8 T cells from cytotoxic effector to quiescent memory metabolic programs. These studies define novel molecular targets that may be exploited to manipulate metabolism, migration and memory function during vaccination.