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Published online before print January 2, 2007

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(Journal of Leukocyte Biology. 2007;81:1102-1110.)
© 2007 by Society for Leukocyte Biology

IL-4 induces a wide-spectrum intracellular signaling cascade in CD8⁺ T cells

Ana Acacia de Sa Pinheiro^*, Alexandre Morrot^*, Sumana Chakravarty^*, Michael Overstreet^*, Jay H. Bream^*, Pablo M. Irusta^,1 and Fidel Zavala^*,1,2

^* Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA; and
Department of Human Science, Georgetown University Medical Center, Georgetown University, Washington, DC, USA

² Correspondence: Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe St., Baltimore, MD 21205, USA. E-mail: fzavala{at}jhsph.edu

IL-4 has distinct effects on the differentiation and functional properties of CD8⁺ T cells. In vivo studies have shown that it is critical for the development of protective memory responses against tumors and infections by Leishmania and Plasmodium parasites. The intracellular signaling events mediated by IL-4/IL-4 receptor (IL-4R) interactions on CD4⁺ T cells have been studied extensively; however, the nature of IL-4-induced signaling on CD8⁺ T cells has not been characterized. Using naïve, activated, as well as differentiated CD8⁺ T cells, we show that IL-4 has a strong in vivo and in vitro antiapoptotic effect on activated and resting CD8⁺ T cells. We demonstrate that IL-4 induces the phosphorylation of the IL-4R, which is followed by the activation of at least two distinct intracellular signaling cascades: the Jak1/STAT6 and the insulin receptor substrate/PI-3K/protein kinase B pathways. We also found that IL-4 induces the Jak3-mediated phosphorylation and nuclear migration of STAT1, STAT3, and STAT5 in naïve, activated, as well as differentiated, IFN--producing CD8⁺ T cells. The induction of this broad signaling activity in CD8⁺ T cells coincides with a transcriptional activity of suppressors of cytokine signaling genes, which are decreased significantly in comparison with CD4⁺ T cells. To our knowledge, this report constitutes the first comprehensive analysis of the signaling events that shape CD8⁺ T cell responses to IL-4.

Key Words: cytokine signaling • CTL • JAK/STAT • PI-3K