IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma.

Abstract

Dense CD4+ T cells isolated from naive mice produce only trace amounts of IL-9 when stimulated by immobilized anti-CD3 in combination with anti-CD28 Abs. In this situation, IL-9 production is significantly stimulated by TGF-beta and further enhanced by the addition of IL-4, which, by itself, has only a minimal influence. IFN-gamma was found to inhibit the enhancing effect of IL-4. However, increasing amounts of IL-4 in the presence of a constant concentration of IFN-gamma could overcome the inhibitory activity of IFN-gamma. The application of CD4+ T cells isolated from IL-2 knockout mice unequivocally revealed that IL-2 is essential for the production of IL-9 by T cells. In addition, the use of T cells from IL-4 knockout mice elucidated that the basic (IL-2 + TGF-beta) mediated IL-9 production is independent of IL-4. Therefore, our results demonstrate that optimal IL-9 production of naive dense CD4+ T cells is positively regulated at different levels: 1) by IL-2, which is essential for IL-9 secretion; 2) followed by TGF-beta, which promotes a considerable increase in IL-9 production above the level induced by IL-2; and 3) finally, by IL-4, which requires the presence of IL-2 and TGF-beta to strongly enhance the production of IL-9. IFN-gamma inhibits the production of IL-9 mainly at the level of IL-4 by neutralizing the effect of this cytokine.

TGF-β Regulation of T Cells

“…In addition to IL-4, IL-1α, IL-1β, IL-18, IL-33, IL-21, IL-6, and IL-10 together with TGF-β also enhance IL-9 production in CD4 + T cells in IL-4-dependent and -independent manners (82)(83)(84). IFN-γ and IL-27, however, are reported to inhibit Th9 differentiation (79,84,85). Interestingly, in polarizing conditions based on TGF-β, stimulation of OX40 promotes differentiation of naive CD4 + T cells toward a Th9 phenotype (86,87), and this costimulatory effect is mediated by the TRAF6 and NF-κB pathways (87).…”

“…Th9 cells produce IL-9 and play important roles in the pathogenesis of allergy and asthma and in antitumor immunity (7,78). Although it was known about two decades ago that TGF-β regulated IL-9 production in CD4 + T cells (79), it was only in 2008 determined to be a critical factor in the differentiation of Th9 cells (80,81). Two groups independently identified that TGF-β and IL-4 are required for Il9 gene activation and Th9 cell differentiation.…”

Regulatory role of T helper 9/interleukin-9: Transplantation view

“…Previously, it was shown that when naive CD4 + T-cell activation is promoted by IL-2, IL-4, and TGF-β, these naive cells start producing IL-9. However, among these three cytokines, TGF-β and IL-2 are the most effective at stimulating the production of IL-9 [ 67 ]. Furthermore, TGF-β is necessary for inducing the expression of PU.1, which positively and negatively regulates the formation of Th9 and Th2 cells, respectively.…”

The Emerging Role of IL-9 in the Anticancer Effects of Anti-PD-1 Therapy

“…This subset of CD4 T cells was identified in 2008 [ 11 , 12 ]. The ability of T H 9 cells to produce IL-9 is greatly attenuated in the absence of IL-2 or STAT5 [ 13 , 14 ]. STAT5 binds to the Il9 promoter, which is necessary for the demethylation of the Il9 locus and its accessibility to other transcription factors [ 15 ].…”

“…Key cytokines inducing IL-9 production by T cells—IL-4 and TGFβ—can be induced by the microbiota and their production can be compromised by antibiotic-driven dysbiosis [ 56 ]. IL-2 is another crucial cytokine for IL-9 production by T cells, it can act in an autocrine or paracrine manner [ 13 , 14 ]. IL-1β can promote IL-9 expression by T H 9 cells in cancer [ 38 ] and induce T H 9 cell differentiation in combination with IL-4 [ 57 ].…”