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CD11b⁺Ly-6C^hi Suppressive Monocytes in Experimental Autoimmune Encephalomyelitis¹

Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

Innate immune cells may regulate adaptive immunity by balancing different lineages of T cells and providing negative costimulation. In addition, CD11b⁺Gr-1⁺ myeloid-derived suppressor cells have been described in tumor, parasite infection, and severe trauma models. In this study, we observe that splenic CD11b⁺ cells markedly increase after experimental autoimmune encephalomyelitis (EAE) immunization, and they suppress T cell proliferation in vitro. Although >80% of CD11b⁺ cells express varying levels of Gr-1, only a small population of CD11b⁺Ly-6C^high inflammatory monocytes (IMC) can efficiently suppress T cell proliferation and induce T cell apoptosis through the production of NO. IFN- produced by activated T cells is essential to induce IMC suppressive function. EAE immunization increases the frequencies of IMC in the bone marrow, spleen, and blood, but not in the lymph nodes. At the peak of EAE, IMC represent 30% of inflammatory cells in the CNS. IMC express F4/80 and CD93 but not CD31, suggesting that they are immature monocytes. Furthermore, IMC have the plasticity to up-regulate NO synthase 2 or arginase 1 expression upon different cytokine treatments. These findings indicate that CD11b⁺Ly-6C^high IMC induced during EAE priming are powerful suppressors of activated T cells. Further understanding of suppressive monocytes in autoimmune disease models may have important clinical implications for human autoimmune diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants AI058680 and AI043496 from National Institute of Allergy and Infectious Diseases, and RG3666 and RG35041 from the National Multiple Sclerosis Society to S.J.K.

² Address correspondence and reprint requests to Dr. Samia J. Khoury, Center for Neurologic Diseases, Brigham and Women’s Hospital, HIM Room 712, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail address: skhoury{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MDSC, myeloid-derived suppressor cells; NOS, NO synthase; 1-MT, 1-methyl tryptophan; 7-AAD, 7-aminoactinomycin D; IDO, indoleamine 2,3-dioxygenase; IMC, inflammatory monocytes; L-NIL, N6-(1-iminoethyl)-L-lysine; L-NMMA, N^G-monomethyl-L-arginine; MOG, myelin oligodendrocyte glycoprotein; nor-NOHA, N-hydroxyl-nor-L-arginine; PD-1, programmed death-1; PGN, peptidoglycan.

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