Naive CD4+ T cells produce interleukin-2 (IL-2) upon stimulation by antigen and antigen-presenting cells but can be induced to differentiate into cells that principally produce interleukin-4 (IL-4) or interferon gamma (IFNgamma). The determination of which lymphokine is dominantly produced has a major impact on the protective value of the immune response. Utilizing naive CD4+ T cells from T cell receptor transgenic mice, it was shown that IL-4 itself is the principal factor determining whether T cells develop into IL-4 producers; in addition, IL-4 strikingly suppresses priming for IFNgamma production. In the absence of IL-4, priming leads to cells that produce moderate amounts of IFNgamma. Addition of IL-12 to the priming culture upregulates priming for IFNgamma production and allows such priming to occur even in the presence of IL-4. The physiologic source of IL-4 that determines this pattern of differentiation is a matter of great importance. A specialized population of splenic CD4+ T cells expressing the NK1.1 marker has been identified and shown to promptly produce IL-4 upon in vivo activation with anti-CD3 antibody or superantigens. Two strains of mice (SJL and beta2-microglobulin knockout mice) have both a deficiency in IL-4 production by these cells and impaired differentiation to the production of IL-4 and to the secretion of IgE implying that these cells have an important role in the production of IL-4 at the outset of immune responses. IL-4 action is mediated by binding to a high affinity receptor. This receptor consists of two chains. One binds IL-4 with substantial affinity and also determines the specificity of the signalling pathway. The other (the gamma chain of the IL-2 receptor or gammac) is essential for transducing biochemical signals. The binding of IL-4 to the IL-4 receptor complex results in the phosphorylation of a 170 kDa substrate, designated 4PS, an analog of insulin receptor substrate-1 (IRS-1). Phosphorylation of 4PS/IRS-1 is lost in truncation mutants of the receptor that delete the most membrane proximal tyrosine. The sequence around that tyrosine is homologous to the sequence around a comparable tyrosine in the insulin and IGF-1 receptors; this motif has been termed the I4R motif. A fusion protein containing the I4R motif binds the substrate and the kinase that can catalyze the phosphorylation of IRS-1. The I4R motif appears to act as a docking site for 4PS/IRS-1.
| 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
