Antigen‐specific Treg regulate Th17‐mediated lung neutrophilic inflammation, B‐cell recruitment and polymeric IgA and IgM levels in the airways

Abstract

Th17 cells play key roles in mediating autoimmunity, inflammation and mucosal host defense against pathogens. To determine whether naturally occurring Treg (nTreg) limit Th17-mediated pulmonary inflammation, OVA-specific CD4 1 Th17 cells and expanded CD4 1 CD25 1 Foxp3 1 nTreg were cotransferred into BALB/c mice that were then exposed to OVA aerosols. Th17 cells, when transferred alone, accumulated in the lungs and posterior mediastinal LN and evoked a pronounced airway hyperreactivity and neutrophilic inflammation, characterized by B-cell recruitment and elevated IgA and IgM levels. Cotransfer of antigen-specific nTreg markedly reduced the Th17-induced pulmonary inflammation and associated neutrophilia, B-cell influx and polymeric Ig levels in the airways, but did not inhibit airway hyperreactivity. Moreover, the regulation appeared restricted to the site of mucosal inflammation, since transfer of nTreg did not affect the Th17 response developing in the lung draining LN, as evidenced by unaltered levels of IL-17 production and low numbers of Foxp3 1 Treg. Our findings suggest a crucial role for Th17 cells in mediating airway B-cell influx and IgA response, and demonstrate that antigen-specific nTreg suppress Th17-mediated lung inflammation. These results provide new insights into how Th17 responses are limited and may facilitate development of novel approaches for controlling Th17-induced inflammation.Key words: B cells . Lung inflammation . Regulation . Treg . Th17 cells Supporting Information available online IntroductionEffector CD4 1 T cells, typically, are characterized as Th1, Th2 and Th17 on the basis of their cytokine profiles. Th1 cells secrete IFN-g and are essential for controlling intracellular pathogens, whereas Th2 cells, which produce IL-4, IL-5 and IL-13, clear helminth infections and orchestrate the inflammatory response in asthma. CD4 1 Th17 cells, which are characterized by their secretion of a distinctive set of effector cytokines including IL-17, IL-17F, IL-21 and IL-22, mediate autoimmunity, inflammation and play a crucial role in mucosal host defense against a diverse range of pathogens [1,2]. Th17 cell differentiation in mice not only requires the inductive cytokines TGF-b and IL-6, but also IL-23 for maturation. Moreover, the differentiation of CD4 1 Foxp3 1 Treg and Th17 cells by TGF-b appears to be reciprocally related, since TGF-b alone promotes expression of the transcription factor Foxp3, whereas the combination of IL-6 and TGF-b suppresses Foxp3 expression and enhances IL-17 production [3]. Other cytokines such as IFN-g and IL-4 have been suggested to SHORT COMMUNICATION Ã These authors contributed equally to this work. [8][9][10]. Although both nTreg and iTreg require IL-2 and TGF-b for their maintenance, the two subsets display different modes of generation and costimulatory requirements [10]. Importantly, the stability of their suppressive function in the presence of IL-6 or IL-4 differs, since nTreg are converted to IL-17-producing (Th17) cells in the presence of , while the ...

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