Arginase-1 is neither constitutively expressed in nor require for myeloid-derived suppressor cell (MDSC)-mediated inhibition of T cell proliferation

Abstract

Abstract Although previous reports suggest that tumor-induced myeloid-derived suppressor cells (MDSC) inhibit T cell proliferation by L-arginine depletion through arginase-1 activity, we herein show that arginase-1 is neither inherently expressed in MDSC nor required for MDSC-mediated inhibition of T cell proliferation. Employing Percoll density gradient centrifugation, large expansions of MDSC in the bone marrow of tumor-bearing mice were isolated and exhibit potent inhibition on T cell proliferation induced via TCR-ligation, Concanavalin A, PMA plus ionomycin, or IL-2. These MDSC, though suppressive toward T cell proliferation, do not hinder TCR-induced IFNγ secretion or granzyme B expression. Despite effectively inhibiting T cell proliferation, both G- and M-MDSC exhibit no arginase-1 expression; however, arginase-1 can be induced by exposure to TCR-activated T cells or their culture medium, but not by T cells activated by other means or growing tumor cells. Western blot analysis revealed that TCR-activated T cells confer arginase-1 expression in MDSC by secreting cytokines that manifest as two distinct signaling-relay axes, IL-6-to-IL-4 or GM-CSF/IL-4-to-IL-10. Specifically, IL-6 signaling increases IL-4R on MDSC, enabling IL-4 to induce arginase-1 expression; similarly, GM-CSF in concert with IL-4 induces IL-10R on MDSC, allowing IL-10-mediated induction. Surprisingly, our data demonstrate that the induction of arginase-1 is not conducive, per se, for MDSC-mediated inhibition of T cell proliferation, as neither supplementation of L-arginine nor arginase-1 inhibitor rescue T cell proliferation. Instead, direct cell contact is required for the inhibition and is not dampened by PD-L1 blockade or SIRPα deficiency.