A CD28-associated signaling pathway leading to cytokine gene transcription and T cell proliferation without TCR engagement.
Stimulation of resting human T cells with the CD28-specific mAb BW 828 induces proliferation and cytokine synthesis without further requirement for TCR coengagement. This observation prompted us to postulate that signal 2 (costimulatory signal) alone without signal 1 (TCR signal) can activate T cells. To test whether this putative function of CD28 is mediated via a particular signaling pathway, we compared early signaling events initiated in resting T cells by the stimulatory mAb BW 828 with signals triggered by the nonstimulating CD28 mAb 9.3. Stimulation of T cells with BW 828 induced an increase in intracellular Ca2+, but did not lead to detectable activation of the protein kinases p56(lck) and c-Raf-1. This pathway resulted in the induction of the transcription factors NF-kappa B, NF-AT, and proteins binding to the CD28 response element of the IL-2 promoter. On the other hand, stimulation of T cells with mAb 9.3 increased the level of intracellular Ca2+ and triggered the activation of p56(lck) and c-Raf-1, but was unable to induce the binding of transcription factors to the IL-2 promoter. In contrast to the differential signaling of BW 828 and 9.3 in resting T cells, the two mAbs exhibited a similar pattern of early signaling events in activated T cells and Jurkat cells (p56(lck) activation, association of phosphatidylinositol 3-kinase with CD28), indicating that the signaling capacity of CD28 changes with activation. These data support the view that stimulation through CD28 can induce some effector functions in T cells and suggest that this capacity is associated with a particular pattern of early signaling events.
Transplantationslabor, Klinik für Abdominal- und Transplantationschirurgie, Medizinische Hochschule Hannover, Germany.
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Siefken
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Klein-Hessling
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Serfling
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Kurrle
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Schwinzer
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018106:CD28 Antigens / Q000276:immunology / Q000502:physiology*; D016207:Cytokines / Q000235:genetics*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007399:Interphase / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors