• Zhen Bian, Ahmed Mansour Abdelaal, Lei Shi, Hongwei Liang, Lanqiao Xiong, Koby Kidder, Mahathi Venkataramani, Courtney Culpepper, Ke Zen, and Yuan Liu.
• Program of Immunology and Molecular Cellular Biology, Department of Biology, Center for Diagnostics and Therapeutics, Center of Inflammation, Immunity and Infection, Georgia State University, Atlanta, GA, USA.
• Eur. J. Immunol. 2018 Jun 1; 48 (6): 1046-1058.

AbstractAlthough previous reports suggest that tumor-induced myeloid-derived suppressor cells (MDSC) inhibit T cells 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. Employing Percoll density gradients, large expansions of MDSC in the bone marrow of tumor-bearing mice were isolated and demonstrated potent inhibition in T-cell proliferation activated by TCR-ligation, Concanavalin A, PMA plus ionomycin, or IL-2. Despite demonstrating characteristic immunosuppressive capacity, these MDSC exhibit no arginase-1 expression and/or exert their inhibitory effects independent of arginase-1 activity. However, arginase-1 expression in MDSC can be induced by exposure to TCR-activated T cells or their culture medium, but not T cells activated by other means or growing tumor cells. Further investigation reveals multiple cytokines secreted by TCR-activated T cells as orchestrating two signaling-relay axes, IL-6-to-IL-4 and GM-CSF/IL-4-to-IL-10, leading to arginase-1 expression in MDSC. Specifically, IL-6 signaling increases IL-4R, enabling IL-4 to induce arginase-1 expression; similarly, GM-CSF in concert with IL-4 induces IL-10R, allowing IL-10-mediated induction. Surprisingly, our study indicates that induction of arginase-1 expression is not conducive to the critical MDSC-mediated inhibition toward T cells, which is rather dependent on direct cell contacts undiminished by PD-L1 blockade or SIRPα deficiency.© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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