Human Th9 differentiation is dependent upon STAT3 to restrain STAT1-mediated inhibition

Publication date: Available online 18 July 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Yuan Zhang, Andrea M. Siegel, Guangping Sun, Tom Dimaggio, Alexandra F. Freeman, Joshua D. Milner

Abstract

Background

Patients with loss of function (LOF) signal transducer and activator of transcription 3 (STAT3) mutations have dermatitis, enhanced IgE production despite a relative lack of immediate hypersensitivity, recurrent infection, and an increased rate of lymphoma, in addition to a number of skeletal and connective tissue abnormalities. Gain of function (GOF) STAT1 mutant patients also have susceptibility to candidiasis and sinopulmonary infection, as well as autoimmunity and squamous cell carcinoma, in addition to even more broad phenotypes.

Objective

Because of the link between Th9 cells and allergic inflammation, autoimmunity and anti-tumor surveillance, and because evidence shows either the role for STAT3 or STAT1 in Th9 differentiation conflicts, we wished to determine the status on this lineage of STAT1GOF and STAT3LOF in humans.

Methods

We detected IL-9 levels and Th9 differentiation of STAT3LOF and STAT1GOF patients, together with Th9 transcript factors, and partially rescued their deficiency in vitro by adding cytokines they lacked or transfecting key molecules.

Results

We found that PBMCs or sorted naïve CD4+ T cells from STAT3LOF and STAT1GOF patients had impaired Th9 generation/differentiation. STAT3 inhibition in normal Th9 cultures diminished early IL-21 induction and late IL-9 production, while exogenous IL-21 enhanced Th9 differentiation even with STAT3 inhibition, by restoring SOCS3 expression and thus inhibiting excessive p-STAT1 activation. Furthermore, exogenous expression of SOCS3 or either T-bet or STAT1 RNAi in STAT3 LOF cells partially rescued IL-9 differentiation.

Conclusion

Collectively, these results suggest that human Th9 differentiation depends on normal p-STAT3 and IL-21 production to suppress p-STAT1 activation and T-bet transcription.

Graphical abstract

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