STAT6 Controls the Number of Regulatory T Cells In Vivo, Thereby Regulating Allergic Lung Inflammation

Abstract

STAT6 plays a central role in IL-4-mediated allergic responses. Several studies indicate that regulatory T cells (Treg) can be modulated by IL-4 in vitro. We previously showed that STAT6−/− mice are highly resistant to allergic lung inflammation even when wild type Th2 effectors were provided and that they have increased numbers of Tregs. However, the role of STAT6 in modulating Tregs in vivo during allergic lung inflammation has not been thoroughly investigated. To investigate Treg and STAT6 interaction during allergic inflammation, STAT6−/−, STAT6×RAG2−/− and RAG2−/− mice were subjected to OVA sensitization and challenge following adoptive transfer of OVA-specific, wild type Th2 effectors with or without prior Treg depletion/ inactivation using anti-CD25 (PC61). As expected, STAT6−/− mice were highly resistant to airway inflammation and remodeling. In contrast, allergic lung inflammation was partially restored in STAT6−/− mice treated with PC61 to levels observed in STAT6×RAG2−/− mice. In some cases, STAT6×RAG2−/− mice were also given natural (n) Tregs along with Th2 effectors. Adoptive transfer of nTregs caused a substantial reduction in BAL eosinophil composition and suppressed airway remodeling and T cell migration into the lung in STAT6×RAG2−/− mice to levels comparable to those in STAT6−/− mice. These results demonstrate the STAT6-dependent suppression of Tregs in vivo in order to promote allergic airway inflammation.

Strategies targeting the IL-4/IL-13 axes in disease

“…STAT6-deficient mice, unable to transduce IL-4 or IL-13 signals, did not develop AHR, mucus hypersecretion or elevations in serum IgE although BAL eosinophils were only partially diminished in a standard sensitization and lung challenge model [86]. STAT-6-deficient mice also had elevated levels of lung T regulatory cells numbers [87] suggesting that IL-4 and IL-13 normally suppress T regulatory cells. When STAT-6 was reconstituted only in the lung epithelia of IL-13-overexpressing mice AHR and mucus hypersecretion, but not BAL eosinophilia or fibrosis, phenotypes returned implicating the epithelium as a key IL-13 target cell type in the asthmatic phenotype [88].…”

“…IL-4 and IL-13 signaling through STAT-6 downregulates T regulatory cell numbers [87]. Atopic patients also have the potential for a skewed immune response to common bacterial antigens.…”

“…In mice IL-4 and IL-13 signaling through STAT-6 has been shown to downregulate lung T regulatory cell numbers [87].…”

Regulatory tone and mucosal immunity in asthma

“…In addition to the induction of OX40L mentioned above, TSLP signaling in DCs can induce STAT6 expression (34). STAT6-/- mice are reported to have an increase in Tregs (69), and STAT6 was further shown to suppress Tregs during allergic lung inflammation in vivo (70, 71). Ray and colleagues also showed an effect of IL-4 and STAT6 on Treg target cells, specifically that STAT6 caused T helper cells to be resistant to Treg-mediated suppression, thereby permitting the development of an adaptive immune response (72).…”

The fate of regulatory T cells: survival or apoptosis

“…Indeed, TGF-b, IL-35 and IL-4 have also been proven to be related to Treg homeostasis. [19][20][21] It is therefore important to consider all the factors related to Treg homeostasis, including cytokines and costimulatory signals, and also take the molecular balance between pro-and anti-apoptotic responses into consideration for the design of effective Treg-based therapeutic strategies. …”