IL-4 acts as a potent stimulator of IFN-γ expression in CD8+ T cells through STAT6-dependent and independent induction of Eomesodermin and T-bet

Abstract

CD8+ T cell synthesis of IFN-γ is an important component of the CD8+ T cell immune response. In short-term cultures of murine pan-T cells, we found that IL-4 was the principal cytokine responsible for driving IFN-γ synthesis by CD3/CD28-activated CD8+ T cells. IL-4 was able to induce low levels of IFN-γ mRNA in CD8+ T cells even in the absence of CD3/CD28 engagement, although concomitant CD3/CD28 stimulation was necessary for IFN-γ secretion. IL-4 induction of IFN-γ was explained by its ability to induce Eomesodermin and T-bet transcription factors whose expression was further increased by CD3/CD28. Expression of Eomesodermin, T-bet and IFN-γ induced by IL-4 was partially dependent upon activation of MAPK and PI3K but independent of the canonical IL-4-activated transcription factor, STAT6. In contrast, expression of IFN-γ induced by IL-4/CD3/CD28 stimulation showed additional dependency upon STAT6 which functions to increase expression of Eomesodermin specifically. These novel findings point to a function for IL-4 as a direct regulator of IFN-γ expression in CD8+ T cells and reveal the molecular mechanisms involved.

Increased Peripheral IL-4 Leads to an Expanded Virtual Memory CD8+ Population

“…point out that this links memory-phenotype cells with IL-15, as IL-15 increases Eomes expression, which in turn increases CD122 expression and therefore sensitivity to IL-15 (25, 26). However, IL-4 also induces Eomes expression in CD8 + T cells (12, 27, 28), as does IL-2 (29). Moreover, the timing of phenotypic changes to naive WT cells transferred to cKO recipients (Fig.…”

Th17 Differentiation and Their Pro-inflammation Function

“…Eomes interacted with GATA3 to prevent its binding to IL-5 promoter in memory Th2 cells or functioned together with T-bet to mediate generation of IFN-γ producing CD8 + cells [62,76,207]. In Th17 cells, ectopic expression of Eomes inhibited Th17 cell differentiation through directly binding to the promoter region of Rorc and Il17.…”

Innate Memory T cells

“…Several of these features can be induced by IL-4 in mature peripheral CD8+ T cells (Kurzweil et al, 2014; Nayar et al, 2012; Oliver, Stolberg, Chensue, & King, 2012; Ventre et al, 2012; Weinreich et al, 2009), suggesting this is not purely a response of CD8+ SP thymocytes. Studies in which CD8+ T cells were exposed to IL-4 suggested that Eomes expression was induced in a STAT6-dependent pathway (Oliver et al, 2012; Ventre et al, 2012).…”

“…Several of these features can be induced by IL-4 in mature peripheral CD8+ T cells (Kurzweil et al, 2014; Nayar et al, 2012; Oliver, Stolberg, Chensue, & King, 2012; Ventre et al, 2012; Weinreich et al, 2009), suggesting this is not purely a response of CD8+ SP thymocytes. Studies in which CD8+ T cells were exposed to IL-4 suggested that Eomes expression was induced in a STAT6-dependent pathway (Oliver et al, 2012; Ventre et al, 2012). The basis by which IL-4 promotes expression of Eomes without T-bet is unclear, but it is interesting to note that studies on lymphopenia-induced proliferation reported that blockade of mTOR led to an increased Eomes:T-bet ratio and slightly reduced expression of CD122 (Li et al, 2011), both which are features of IL-4-induced memory CD8+ T cells.…”