Antigen presenting cell‐derived IL‐6 restricts Th2‐cell differentiation

Abstract

The identification of DC-derived signals orchestrating activation of Th1 and Th17 immune responses has advanced our understanding on how these inflammatory responses develop. However, whether specific signals delivered by DCs also participate in the regulation of Th2 immune responses remains largely unknown. In this study, we show that administration of antigen-loaded, IL-6-deficient DCs to naïve mice induced an exacerbated Th2 response, characterized by the differentiation of GATA-3-expressing T lymphocytes secreting high levels of IL-4, IL-5, and IL-13. Coinjection of wild type and IL-6-deficient bone marrow-derived dendritic cells (BMDCs) confirmed that IL-6 exerted a dominant, negative influence on Th2-cell development. This finding was confirmed in vitro, where exogenously added IL-6 was found to limit IL-4-induced Th2-cell differentiation. iNKT cells were required for optimal Th2-cell differentiation in vivo although their activation occurred independently of IL-6 secretion by the BMDCs. Collectively, these observations identify IL-6 secretion as a major, unsuspected, mechanism whereby DCs control the magnitude of Th2 immunity.Keywords: Airway allergy r DCs r IL-6 r iNKT cells r Th2-cell differentiation Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe role of APCs, and in particular DCs, in regulating naïve Th-cell differentiation into the Th2 lineage remains poorly understood. Indeed, although DCs represent the major source of Th1-and Th17-polarizing cytokines (such as [1], these cells do not appear to produce the most efficient and best characterized pro-Th2 soluble factors (such as Correspondence: Dr. Fabienne Andris e-mail: fandris@ulb.ac.be or thymic stromal lymphopoietin) identified to date. Thus, although numerous studies have illustrated the role of several innate cell types, including basophils and DC subtypes (conventional CD8α − DCs, inflammatory monocyte-derived FcεRI + DCs, CD301b + , PDL2 + , and/or MGL2 + dermal DCs) in driving Th2-cell differentiation in vivo [2][3][4][5][6][7][8][9][10][11][12], the mechanisms by which APCs promote Th2-type responses in vivo remain ill-defined. * These authors contributed equally to this work as first authors. * * These authors contributed equally to this work as senior authors.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 3252-3262 Cellular immune response 3253The Th2 pathway has therefore been often considered as a "default pathway," mostly based on the observation that stimulation of naïve T cells in the absence of strong Th1-polarizing conditions (such as lack of APC-derived IL-12 [2,13]) favors the acquisition of a Th2 phenotype in several experimental models. This simple concept has been recently challenged, since several APC-derived, pro-Th2 instructing signals have been identified (OX40L, ICOS-L, the Notch family member Jagged-1, or the T-cell immunoglobulin and mucin domain molecule-4 [14-17]), although their relat...

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