Indispensable Role of Stat5a in Stat6-Independent Th2 Cell Differentiation and Allergic Airway Inflammation

Abstract

It is well-recognized that Stat6 plays a critical role in Th2 cell differentiation and the induction of allergic inflammation. We have previously shown that Stat5a is also required for Th2 cell differentiation and allergic airway inflammation. However, it is the relative importance and redundancy of Stat6 and Stat5a in Th2 cell differentiation and allergic airway inflammation are unknown. In this study we addressed these issues by comparing Stat5a-deficient (Stat5a−/−) mice, Stat6−/− mice, and Stat5a- and Stat6 double-deficient (Stat5a−/− Stat6−/−) mice on the same genetic background. Th2 cell differentiation was severely decreased in Stat6−/−CD4+ T cells, but Stat6-independent Th2 cell differentiation was still significantly observed in Stat6−/−CD4+ T cells. However, even in the Th2-polarizing condition (IL-4 plus anti-IFN-γ mAb), no Th2 cells developed in Stat5a−/−Stat6−/− CD4+ T cells. Moreover, Ag-induced eosinophil and lymphocyte recruitment in the airways was severely decreased in Stat5a−/−Stat6−/− mice compared with that in Stat6−/− mice. These results indicate that Stat5a plays an indispensable role in Stat6-independent Th2 cell differentiation and subsequent Th2 cell-mediated allergic airway inflammation.

STAT6 Deletion Converts the Th2 Inflammatory Pathology Afflicting LatY136F Mice into a Lymphoproliferative Disorder Involving Th1 and CD8 Effector T Cells

“…The small population of Lat Y136F Stat6 Ϫ/Ϫ Th2 effectors that develop in parallel to the dominant Th1 cells might correspond to cells in which the levels of T-bet were lower than the threshold required for inhibiting basal levels of GATA-3 and Th2 differentiation. Similar to the situation observed in in Lat Y136F Stat6 Ϫ/Ϫ mice, it has been recently reported that in some situations Th2 differentiation occurs in a manner independent of STAT6 (32)(33)(34). The Th1 and CD8 T cells that dominate the lymphoid compartment of Lat Y136F Stat6 Ϫ/Ϫ mice and are capable of producing IFN-␥ were unable to suppress the development of these few Th2 cells.…”

Marked Induction of c-Maf Protein during Th17 Cell Differentiation and Its Implication in Memory Th Cell Development

“…1B), Maf, Rorc and Rora were all high in Factor 2 but low in Factor 1. In contrast, Gata3, which encodes the master regulator transcription factor of Th2 cells, was very high in Factor 1 but low in Factor 2, and so was Stat5a, which is implicated in Th2 differentiation (29,30). From these data, we may safely call Factor 1 "a Th2-related factor" and Factor 2 "a Th17-related factor".…”

The PPE18 Protein of Mycobacterium tuberculosis Inhibits NF-κB/rel–Mediated Proinflammatory Cytokine Production by Upregulating and Phosphorylating Suppressor of Cytokine Signaling 3 Protein

“…Recently, SOCS3 has also been found to inhibit TNFR-associated factor 6 and TGF-b-activated kinase, both of which are crucial for TLR-driven proinflammatory responses (34). Owing to the importance of SOCS3 protein in the regulation of innate and adaptive immunity (26,29,35,76), it is believed that the microorganisms may have evolved strategies to hijack the SOCS3 signaling system also for evasion of the host's immune response. Even though mycobacteria species are suggested to trigger SOCS3 expression (25,31,32), the pathophysiological role of SOCS3 in tuberculosis is not well understood.…”

“…It appears that PPE18 probably targets the proinflammatory signaling downstream of TLR2 by activating certain negative regulators of this pathway. Interestingly, suppressor of cytokine signaling 3 (SOCS3) downstream of TLR2 (25) acts as negative regulator of proinflammatory signaling (26)(27)(28)(29). Because several pathogenic mycobacterial species induce expression of the SOCS3 protein (30)(31)(32), we speculated that probably SOCS3 protein is involved in the suppression of induction of IL-12 p40 in macrophages treated with PPE18.…”