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Distinct regions in the CD28 cytoplasmic domain are required for T helper type 2 differentiation

Abstract

CD28 costimulation is essential for CD4+ T cell proliferation, survival, interleukin 2 (IL-2) production and T helper type 2 development. To define the nature of the signals that may drive different T cell responses, we have done a structure-function analysis of the CD28 cytoplasmic tail in primary T cells. CD28-mediated T cell proliferation and IL-2 production did not require a particular cytoplasmic domain. In contrast, IL-4 production was driven by the cooperative activity of specific motifs within the CD28 cytoplasmic tail. Using a gene-complementation approach, we provide evidence that one component of this T helper type 2 differentiation signal was mediated by 3-phosphoinositide-dependent protein kinase 1. Thus, different mechanisms underlie the induction of distinct T cell functional responses by CD28.

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Figure 1: Expression of the CD28 structural domain mutants in CD28-deficient cells.
Figure 2: CD28-mediated IL-2 production is regulated by redundant signaling domains.
Figure 3: CD28-mediated proliferation is regulated by redundant signaling domains.
Figure 4: Specific signaling motifs are required for CD28-mediated IL-4 production.
Figure 5: CD28 cytoplasmic tail binding motifs act cooperatively to drive IL-4 production.
Figure 6: PDK-1 restores IL-4 production to CD28-deficient cells expressing Y170,188F or P189,190A.

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Acknowledgements

We thank S.W. Jiang and C. McArthur for technical assistance. Supported by National Institutes of Health (RO1 AI25022 (A.K.A.) and K08 DK62343-01 (P.G.A.)), Howard Hughes Postdoctoral Research Fellowship for Physicians (P.G.A.), Abbott Scholar Award in Rheumatology Research (A.N.) and Rosalind Russell Medical Research Center for Arthritis (A.N., L.K., A.W., A.S. and J.I.).

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Correspondence to Abul K Abbas.

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Andres, P., Howland, K., Nirula, A. et al. Distinct regions in the CD28 cytoplasmic domain are required for T helper type 2 differentiation. Nat Immunol 5, 435–442 (2004). https://doi.org/10.1038/ni1044

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