Serine Is an Essential Metabolite for Effector T Cell Expansion.

Abstract

During immune challenge, T lymphocytes engage pathways of anabolic metabolism to meet the demands of clonal expansion and development of effector functions. Here we report a critical role for the non-essential amino acid serine in effector T cell responses. Upon activation, T cells upregulate enzymes of the serine, glycine, one-carbon (SGOC) metabolic network, and rapidly increase processing of serine into one-carbon metabolism. We show that T cell proliferation is highly dependent on extracellular serine, and that serine is required for optimal T cell expansion even in glucose concentrations sufficient to support T cell activation, bioenergetics, and effector function. Restricting dietary serine impairs pathogen-driven expansion of T cells in vivo, without affecting overall immune cell homeostasis. Mechanistically, we demonstrate that serine supplies glycine and one-carbon units for de novo nucleotide biosynthesis in proliferating T cells, and that one-carbon units from formate can rescue T cells from serine deprivation. Our data implicate serine as a key immunometabolite that directly modulates adaptive immunity by controlling T cell proliferative capacity.