SRC2 controls CD4⁺ T cell activation via stimulating c-Myc-mediated upregulation of amino acid transporter <i>Slc7a5</i>.

Abstract

T cell activation stimulates substantially increased protein synthesis activity to accumulate sufficient biomass for cell proliferation. The protein synthesis is fueled by the amino acids transported from the environment. Steroid nuclear receptor coactivator 2 (SRC2) is a member of a family of transcription coactivators. Here, we show that SRC2 recruited by c-Myc enhances CD4⁺ T cell activation to stimulate immune responses via upregulation of amino acid transporter Slc7a5. Mice deficient of SRC2 in T cells (<i>SRC2^fl/fl/CD4^Cre</i>) are resistant to the induction of experimental autoimmune encephalomyelitis (EAE) and susceptible to <i>Citrobacter rodentium</i> (<i>C. rodentium</i>) infection. Adoptive transfer of naive CD4⁺ T cells from <i>SRC2^fl/fl/CD4^Cre</i> mice fails to elicit EAE and colitis in <i>Rag1^/</i> recipients. Further, CD4⁺ T cells from <i>SRC2^fl/fl/CD4^Cre</i> mice display defective T cell proliferation, cytokine production, and differentiation both in vitro and in vivo. Mechanically, SRC2 functions as a coactivator to work together with c-Myc to stimulate the expression of amino acid transporter Slc7a5 required for T cell activation. Slc7a5 fails to be up-regulated in CD4⁺ T cells from <i>SRC2^fl/fl/CD4^Cre</i> mice, and forced expression of <i>Slc7a5</i> rescues proliferation, cytokine production, and the ability of <i>SRC2^fl/fl/CD4^Cre</i> CD4⁺ T cells to induce EAE. Therefore, SRC2 is essential for CD4⁺ T cell activation and, thus, a potential drug target for controlling CD4⁺ T cell-mediated autoimmunity.