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STAT6 Activation Confers upon T Helper Cells Resistance to Suppression by Regulatory T Cells

Brendan B.L. Pillemer^*, Zengbiao Qi^*, Barbro Melgert, Timothy B. Oriss^*, Prabir Ray^*, and Anuradha Ray^*,

^*Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and University Medical Center Groningen, Department of Pathology and Laboratory Medicine, Groningen, The Netherlands; and Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213

Recent studies have highlighted characteristics of T regulatory cells (Tregs) that underlie their suppressive function. However, mechanisms that override their suppressive function in the context of an adaptive immune response are not well understood. In the lungs of mice undergoing allergic inflammation, appreciable numbers of Tregs were identified that possessed suppressive function when assayed ex vivo. We investigated whether the Th2-promoting cytokine IL-4 played a permissive role that superseded Treg function, thereby allowing the development of allergic inflammation. IL-4 signaling via the IL-4R-STAT6 axis was required to maintain Foxp3 expression in Tregs and promote their proliferation. However, the results of both in vivo experiments involving adoptive transfer of Tregs into Ag-sensitized vs naive animals and in vitro suppression assays performed with or without exogenous IL-4 showed the ability of IL-4 to compromise Treg-mediated suppression. Use of retrovirally expressed, constitutively active STAT6 revealed that the underlying mechanism was not IL-4-mediated dysfunction of Tregs but involved the resistance of Th cells to Treg-mediated suppression that would permit the development of an adaptive immune response. Our data suggest that infectious tolerance, mediated by membrane-bound TGF-β expressed by Tregs, is compromised by the competing effects of IL4-induced signaling in naive CD4⁺ Th cells.

Address correspondence and reprint requests to Dr. Anuradha Ray, Department of Medicine, Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Montefiore University Hospital A628 Northwest, Pittsburgh, PA 15213. E-mail address: raya{at}pitt.edu.

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