STAT6 Signaling Attenuates Interleukin-17-Producing γδ T Cells during Acute Klebsiella pneumoniae Infection

Abstract

A pproximately 50% of the intraepithelial lymphocyte population is composed of ␥␦ T cells, which constitute a critical first line of defense against bacterial and fungal pathogens (1). In contrast to adaptive ␣␤ T cells, ␥␦ T cells are capable of immediate cytokine release, providing an initial innate layer of protection at mucosal surfaces while influencing the development of subsequent adaptive responses (2, 3). ␥␦17 cells are a subset of ␥␦ T cells that produce large quantities of interleukin-17A (IL-17A), a cytokine crucial to antibacterial and antifungal defense (4). ␥␦17 cells also produce high levels of IL-17A in various models of inflammation and autoimmunity, including experimental autoimmune encephalitis, ischemic brain injury, and psoriasis (2, 3, 5-7). While these data highlight the importance of understanding how ␥␦17 cell function is regulated, this process remains poorly understood.␥␦17 cell function is controlled by multiple immune cell populations and soluble molecules, particularly cytokines. Within 4 to 8 h in the presence of the inflammatory cytokines IL-23 and IL-1␤, ␥␦17 cells secrete IL-17A without the need for T cell receptor (TCR) engagement (2). ␥␦17 cells constitutively express IL-23 receptor (IL-23R) and IL-1R1, providing for an efficient mechanism to induce rapid effector cytokine production. A recent study showed that the serine/threonine kinase Sgk1 is a novel, critical regulator of IL-23R expression (8).Studies from our group and others have established that STAT6 negatively regulates IL-17A expression in Th17 cells (9-13). By extension, we hypothesized that STAT6 also inhibits innate ␥␦17 cell cytokine secretion. STAT6 is a transcription factor important for Th2 differentiation, inhibiting Th1 differentiation and activating the B cell response (14). IL-4 signals through both the type I IL-4 receptor (IL-4R), which consists of IL-4R␣ and the common ␥-chain, and the type II IL-4R, which consists of IL-4R␣ and IL-13R␣, while IL-13 signals through only the type II IL-4R (15, 16). IL-4 binds to the IL-4R␣ subunit and IL-13 binds to the IL-13R␣ subunit of the IL-4 heterodimer receptor with high affinity, leading to the phosphorylation of STAT6 (17,18). STAT6 is expressed at high levels in the settings of parasitic infections (19) and asthma, during which STAT6 induces Th2 differentiation, IgE antibody class switching, goblet cell metaplasia, alternative macrophage activation, mucus expression, and airway remodeling (20). Thus, STAT6 attenuation of ␥␦17 cell function may impair host defenses against bacterial and fungal infections in people with asthma or parasitic infections.We found that ␥␦17 cells expressed the type I IL-4R, and that IL-4 increased STAT6 phosphorylation in ␥␦17 cells. Furthermore, IL-4 signaling attenuated ␥␦17 cell production of IL-17A and IL-17F. IL-4 also decreased ␥␦17 cell expression of IL-23R as well as Sgk1. To determine whether STAT6 regulates ␥␦17 cell cytokine expression in vivo, we used a mouse model of Klebsiella pneumoniae lung infection in mice deficien...

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