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Differentiation of naive CD4 T cells into T helper (Th) 2 cells requires signaling through the T cell receptor and an appropriate cytokine environment. IL-4 is critical for such Th2 differentiation. We show that IL-2 plays a central role in this process. The effect of IL-2 on Th2 generation does not depend on its cell growth or survival effects. Stat5[a.sup.-/-] cells show diminished differentiation to IL-4 production, and forced expression of a constitutively active form of Stat5a replaces the need for IL-2, In vivo IL-2 neutralization inhibits IL-4 production in two models. Studies of restriction enzyme accessibility and binding of Stat5 to chromatin indicate that IL-2 mediates its effect by stabilizing the accessibility of the Il4 gene. Thus, IL-2 plays a critical role in the polarization of naive CD4 T cells to the Th2 phenotype.

[CD4.sup.+] T cells from T cell receptor transgenic mice that have been vigorously primed to be interleukin (IL)-4 producers ([T.sub.H2] cells) are capable of producing IL-4 even if restimulated in the absence of IL-4 and in the presence of IL-12. T cells vigorously primed in the absence of IL-4 ([T.sub.H1] cells) fail to produce IL-4 even if restimulated under conditions that would cause a naive T cell to produce IL-4. In contrast, interferon [Gamma] (IFN-[Gamma]) production is highly cytokine-regulated. T cells primed in the presence of IL-4 develop into IFN-[Gamma] producers if IFN-[Gamma] is included in the priming culture and if the cells are challenged in the presence of IL-12, presumably reflecting the role of IFN-[Gamma] in inducing responsiveness to IL-12. Cells primed in the absence of IL-4 become highly responsive to IL-12 if IFN-[Gamma] is included in the priming culture, and these cells are excellent IFN-[Gamma] producers upon challenge; IL-12 considerably enhances their production of IFN-[Gamma]. If cells are primed in the absence of IL-4 and IFN-[Gamma], they show very weak responsiveness to IL-12 as determined by STAT-4 activation. However, these cells acquire IL-12 responsiveness if cultured with IFN-[Gamma] for a period as short as 4 hr. Thereafter, they produce large amounts of IFN-[Gamma] upon challenge with antigen in the presence of IL-12. These results indicate that in primed [CD4.sup.+] T cells, IL-4 production is largely cytokine-autonomous, whereas IFN-[Gamma] production is highly cytokine-regulated.

A study demonstrates that the acute generation interleukin 2(IL-1) and interferon-gamma (IFN-gamma) by naive CD4+ and CD8+ T cells in response to accessory cell-dependent activation with soluble anti-CD3 is strongly inhibited by IL-4. The IL-2 generation in response to antigen and antigen-presenting cells (APCs) of T cells from T-cell antigen receptor (TCR)-transgenic mice is inhibited by IL-4. IL-2 and IFN-gamma generation by primed T cells or T-cell clones or by naive T cells activated with phorbol ester and calcium ionophore in response to antigen plus APCs are not inhibited by IL-4.

Type 2 helper T cells (TH2 cells) produce interleukin 13 (IL-13) when stimulated by papain or house dust mite extract (HDM) and induce eosinophilic inflammation. This innate response is dependent on IL-33 but not T cell antigen receptors (TCRs). While type 2 innate lymphoid cells (ILC2 cells) are the dominant innate producers of IL-13 in naive mice, we found here that helminth-infected mice had more TH2 cells compared to uninfected mice, and thes e cells became major mediators of innate type 2 responses. TH2 cells made important contributions to HDM-induced antigen-nonspecific eosinophilic inflammation and protected mice recovering from infection with Ascaris suum against subsequent infection with the phylogenetically distant nematode Nippostrongylus brasiliensis. Our findings reveal a previously unappreciated role for effector TH2 cells during TCR-independent innate-like immune responses. [ABSTRACT FROM AUTHOR]

Innate lymphoid cells (ILCs) are lymphocyte-like cells that lack T cell or B cell antigen receptors and mediate protective and repair functions through cytokine secretion. Among these, type 2 ILCs (ILC2 cells) are able to produce type 2 cytokines. We report the existence of an inflammatory ILC2 (iILC2) population responsive to interleukin 25 (IL-25) that complemented IL-33-responsive natural ILC2 (nILC2) cells. iILC2 cells developed into nILC2-like cells in vitro and in vivo and contributed to the expulsion of Nippostrongylus brasiliensis. They also acquired IL-17-producing ability and provided partial protection against Candida albicans. We propose that iILC2 cells are transient progenitors of ILCs mobilized by inflammation and infection that develop into nILC2-like cells or ILC3-like cells and contribute to immunity to both helminths and fungi. [ABSTRACT FROM AUTHOR]