Interleukin 4: signalling mechanisms and control of T cell differentiation.
Interleukin 4 (IL-4) is a pleiotropic type I cytokine that controls both growth and differentiation among haemopoietic and non-haemopoietic cells. Its receptor is a heterodimer. One chain, the IL-4R alpha chain, binds IL-4 with high affinity and determines the nature of the biochemical signals that are induced. The second chain, gamma c, is required for the induction of such signals. IL-4-mediated growth depends upon activation events that involve phosphorylation of Y497 of IL-4R alpha, leading to the binding and phosphorylation of 4PS/IRS-2 in haemopoietic cells and of IRS-1 in non-haemopoietic cells. By contrast, IL-4-mediated differentiation events depend upon more distal regions of the IL-4R alpha chain that include a series of STAT-6 binding sites. The distinctive roles of these receptor domains was verified by receptor-reconstruction experiments. The 'growth' and 'differentiation' domains of the IL-4R alpha chain, independently expressed as chimeric structures with a truncated version of the IL-2R beta chain, were shown to convey their functions to the hybrid receptor. The critical role of STAT-6 in IL-4-mediated gene activation and differentiation was made clear by the finding that lymphocytes from STAT-6 knockout mice are strikingly deficient in these functions but have retained the capacity to grow, at least partially, in response to IL-4. IL-4 plays a central role in determining the phenotype of naive CD4+ T cells. In the presence of IL-4, newly primed naive T cells develop into IL-4 producers while in its absence they preferentially become gamma-interferon (IFN-gamma) producers. Recently, a specialized subpopulation of T cells, CD4+/NK1.1+ cells, has been shown to produce large amounts of IL-4 upon stimulation. Two examples of mice with deficiencies in these cells are described--beta 2-microglobulin knockout mice and SJL mice. Both show defects in the development of IL-4-producing cells and in the increase in serum IgE in response to stimulation with the polyclonal stimulant anti-IgD. Both sets of mice have major diminutions in the number of CD4+/ NK1.1+ T cells, strongly indicating an important role of these cells in some but not all IgE responses to physiologic stimuli.
Paul
W E
WE
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation; D002455:Cell Division; D016207:Cytokines / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D018123:Receptors, Interleukin / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000502:physiology; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D015534:Trans-Activators / Q000502:physiology
D015703:Antigens, CD; D016207:Cytokines; D018123:Receptors, Interleukin; D015375:Receptors, Interleukin-2; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4