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Human Anti-Inflammatory Macrophages Induce Foxp3⁺GITR⁺CD25⁺ Regulatory T Cells, Which Suppress via Membrane-Bound TGFβ-1¹

Nigel D. L. Savage^2,*,, Tjitske de Boer^*,, Kimberley V. Walburg, Simone A. Joosten^*,, Krista van Meijgaarden^*,, Annemiek Geluk^*, and Tom H. M. Ottenhoff^2,*,

^* Department of Immunohematology and Blood Transfusion and Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

CD4⁺ T cell differentiation and function are critically dependent on the type of APC and the microenvironment in which Ag presentation occurs. Most studies have documented the effect of dendritic cells on effector and regulatory T cell differentiation; however, macrophages are the most abundant APCs in the periphery and can be found in virtually all organs and tissues. The effect of macrophages, and in particular their subsets, on T cell function has received little attention. Previously, we described distinct subsets of human macrophages (pro- and anti-inflammatory, m1 and m2, respectively) with highly divergent cell surface Ag expression and cytokine/chemokine production. We reported that human m1 promote, whereas m2 decrease, Th1 activation. Here, we demonstrate that m2, but not m1, induce regulatory T cells with a strong suppressive phenotype (T_m2). Their mechanism of suppression is cell-cell contact dependent, mediated by membrane-bound TGFβ-1 expressed on the regulatory T cell (Treg) population since inhibition of TGFβ-1 signaling in target cells blocks the regulatory phenotype. T_m2, in addition to mediating cell-cell contact-dependent suppression, express typical Treg markers such as CD25, glucocorticoid-induced TNF receptor (GITR), and Foxp3 and are actively induced by m2 from CD25-depleted cells. These data identify m2 cells as a novel APC subset capable of inducing Tregs. The ability of anti-inflammatory macrophages to induce Tregs in the periphery has important implications for understanding Treg dynamics in pathological conditions where macrophages play a key role in inflammatory disease control and exacerbation.

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 the Netherlands Organization for Scientific Research (NWO) and The Netherlands Leprosy Relief Foundation (NLR).

² Address correspondence and reprint requests to Prof. dr T. H. M. Ottenhoff and Dr. N. D. L. Savage, Departments of Immunohematology and Blood Transfusion and Infectious Diseases, Leiden University Medical Center, E3-Q, 2 Albinusdreef, 2333ZA Leiden, The Netherlands. E-mail addresses: T.H.M.Ottenhoff{at}lumc.nl and N.D.L.Savage{at}lumc.nl

³ Abbreviations used in this paper: Treg, regulatory T cell; GITR, glucocorticoid-induced TNF receptor; LAP, latency-associated peptide; m1/2, pro- and anti-inflammatory macrophages, respectively; mTGFβ-1, membrane TGFβ-1; nTreg, naturally occurring T regulatory cell; T_Ind, indicator responder T cell; T_m1/2, allogeneic T cells raised against m1/2 cells.

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