TGF-β1 produced by alternatively activated macrophages synchronizes a tolerogenic iTreg-Th17 cell axis

• Published in: The Journal of immunology (1950) Vol. 196; no. 1_Supplement; pp. 56 - 56.7
• Main Authors: Haribhai, Dipica, Ziegelbauer, Jennifer, Williams, Calvin B
• Format: Journal Article
• Language: English
• Published: 01.05.2016
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.196.Supp.56.7

Abstract Induced regulatory T (iTreg) cells and T helper 17 (Th17) cells develop at mucosal interfaces. While iTreg cells are required for the maintenance of mucosal tolerance, Th17 cells can play divergent roles. Both iTreg and Th17 cells require TGF-β1 for their differentiation. Importantly, the primary source of TGF-β1 in vivo is unknown. Here, we investigate the mechanisms that control iTreg and Th17 cell development. We hypothesize that alternatively activated M2a macrophages support mucosal tolerance through TGF-β1 mediated expansion of both iTreg and Th17 cells. We pretreat Rag1­­−/− C57BL/6 mice prior to colitis induction or treat mice with established disease with polarized macrophages. In some experiments the macrophages lacked the capacity to produce TGF-β1. Weight loss, colitis disease scores, and FACS analysis of mesenteric lymph nodes and gut infiltrates were used to evaluate the impact of macrophage therapy on the expansion and function of the iTreg-Th17 cell axis. Pre-conditioning mice with M2a but not M1 macrophages resulted in a 16-fold increase in the number of iTreg cells and a 8-fold increase in the number of Th17 cells when compared to control mice. This expansion required TGF-β1 produced by both the transferred M2a cells and by host myeloid cells. Established colitis was successfully treated by concomitant M2a and nTreg cell transfers, but not by nTreg cell transfers alone. In conclusion, M2a macrophages that produce TGF-β1 regulate development of a tolerogenic iTreg-Th17 cell axis. The change in iTreg and Th17 cells numbers linked to M2a macrophage polarization is directionally concordant and dependent on T cell produced IL17A, confirming that both iTreg and Th17 cells are required to mediate intestinal homeostasis.