Interleukin 4: Signalling Mechanisms and Control of T Cell Differentiation

  1. Gregory R. Bock Organizer and
  2. Jamie A. Goode
  1. William E. Paul

Published Online: 28 SEP 2007

DOI: 10.1002/9780470515280.ch14

Ciba Foundation Symposium 204 - The Molecular Basis of Cellular Defence Mechanisms

Ciba Foundation Symposium 204 - The Molecular Basis of Cellular Defence Mechanisms

How to Cite

Paul, W. E. (2007) Interleukin 4: Signalling Mechanisms and Control of T Cell Differentiation, in Ciba Foundation Symposium 204 - The Molecular Basis of Cellular Defence Mechanisms (eds G. R. Bock and J. A. Goode), John Wiley & Sons, Ltd., Chichester, UK. doi: 10.1002/9780470515280.ch14

Author Information

  1. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

Publication History

  1. Published Online: 28 SEP 2007

ISBN Information

Print ISBN: 9780471965671

Online ISBN: 9780470515280

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Keywords:

  • interleukin 4;
  • T cell differentiation;
  • lymphocytes;
  • differentiation;
  • growth

Summary

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-4Rα chain, binds IL-4 with high affinity and determines the nature of the biochemical signals that are induced. The second chain, γc, is required for the induction of such signals. IL-4-mediated growth depends upon activation events that involve phosphorylation of Y497 of IL-4Rα, 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-4Rα 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-4Rα chain, independently expressed as chimeric structures with a truncated version of the IL-2Rβ 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 naïve T cells develop into IL-4 producers while in its absence they preferentially become γ-interferon (IFN-γ) 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—β2-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.