Interleukin-4 (IL-4) is a multifunctional type I cytokine that mediates its function through a heterodimeric receptor consisting of the IL-4 receptor (R) alpha chain and the gammac chain. IL-4 mediated growth regulation depends upon an IL-4R alpha receptor domain centering on Y497. When Y497 is phosphorylated, it acts as a docking site for a series of PTB-domain-containing proteins including IRS-1, IRS-2, Shc, and the newly identified IL-4 receptor interacting protein (FRIP). IRS-1, IRS-2 and Shc mediate their function, in part, by enhancing the action of the RAS pathway, through the conversion of RAS-GDP to RAS-GTP. FRIP is a PTB-domain containing protein that binds to RAS-GAP. RAS-GAP catalyzes the hydrolysis of RAS-GTP to RAS-GDP and thus limits growth mediated through the RAS pathway. Results drawn from the study of mice expressing low levels of FRIP suggest that the IL-4 mediated phosphorylation of FRIP down-regulates IL-4-induced growth, implying that FRIP enhances the activity of RAS-GAP. These results strongly suggest that IL-4-mediated growth regulation is under very strong positive and negative regulation, both depending upon substrate phosphorylation mediated by receptor activation. This type of regulation could provide a mechanism for the precise tuning of IL-4-mediated growth. FRIP has recently been shown to be phosphorylated in response to IL-2 and IL-3; preliminary results suggest it is also activated by the T cell receptor, indicating that it may have very broad activities in regulating lymphocyte growth control. IL-4-mediated gene activation and differentiation depend upon an independent domain of the IL-4Ralpha chain containing three STAT-6 binding sites. Development of naive T cells into IL-4-producing cells is dependent upon IL-4 itself. IL-4Ralpha chain knockout mice display a major impairment in the development of TH2-type immune responses in response to infection with Nippostrongylus brasiliensis. These mice do possess a set of CD4+, CD62L-low cells that can secrete some IL-4 in response to stimulation with anti-CD3; these cells may be a set of conventional T cells that can become IL-4-producers without a requirement for IL-4 and may act to aid naive cells to develop into IL-4 producing TH2 cells. A second population potentially important in this respect are CD4+, NK1.1+ T cells, largely specific for CD-1 and enriched in cells that use Vbeta8 and Valpha14 chains in their T cell receptors. These cells are numerous among liver, Peyer's patch and portal blood T cells, suggesting that they play a particularly important role in immune responses mediated by gut lymphoid tissue. Interestingly, they are rare in mesenteric lymph node and, indeed, among all lymph node cells. A population of CD4+ T cells that have essentially identical properties, except that they lack the expression of NK1.1, are found in normal mice in a frequency similar to those that do express NK1.1. The development of naive TH precursor cells into TH1 and TH2 cells is a highly regulated process, with the acquisition of IL-4 and IFNgamma-producing activities being independently controlled. Fully differentiated TH1 cells fail to acquire IL-4-producing capacity even when cultured with antigen in the presence of IL-4. It has now been shown that fully differentiated TH1 cells display a desensitized IL-4R. IL-4 fails to elicit STAT-6 phosphorylation in such cells. Interestingly, these cells also are deficient in IRS-2, as are cells of STAT-6 KO mice that have been stimulated in vitro in with IL-4. Thus, the induction of the major growth regulatory substrate phosphorylated in response to IL-4 is under the control of STAT-6, explaining how the gene activation function of the IL-4 receptor plays a role in controlling growth.
| Dewas, Cedric; Chen, Xi; Honda, Tetsuya et al. (2015) TSLP expression: analysis with a ZsGreen TSLP reporter mouse. J Immunol 194:1372-80 |
| Paul, William E (2014) Endless fascination. Annu Rev Immunol 32:1-24 |
| Ben-Sasson, S Z; Wang, K; Cohen, J et al. (2013) IL-1? strikingly enhances antigen-driven CD4 and CD8 T-cell responses. Cold Spring Harb Symp Quant Biol 78:117-24 |
| Paul, William E; Milner, Joshua D; Grossman, Zvi (2013) Pathogen-sensing, regulatory T cells, and responsiveness-tuning collectively regulate foreign- and self-antigen mediated T-cell responses. Cold Spring Harb Symp Quant Biol 78:265-76 |
| van Panhuys, Nicholas; Prout, Melanie; Forbes, Elizabeth et al. (2011) Basophils are the major producers of IL-4 during primary helminth infection. J Immunol 186:2719-28 |
| Guo, Liying; Wei, Gang; Zhu, Jinfang et al. (2009) IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci U S A 106:13463-8 |
| Zhu, Jinfang; Davidson, Todd S; Wei, Gang et al. (2009) Down-regulation of Gfi-1 expression by TGF-beta is important for differentiation of Th17 and CD103+ inducible regulatory T cells. J Exp Med 206:329-41 |
| Ben-Sasson, Shlomo Z; Hu-Li, Jane; Quiel, Juan et al. (2009) IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci U S A 106:7119-24 |
| Milner, Joshua D; Brenchley, Jason M; Laurence, Arian et al. (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452:773-6 |
| Min, Booki; Paul, William E (2008) Basophils and type 2 immunity. Curr Opin Hematol 15:59-63 |
Showing the most recent 10 out of 66 publications
