International Immunology, Vol. 15, No. 5, pp. 655-663,
May 2003
© 2003 Japanese Society for Immunology
Mitogenic signals through CD28 activate the protein kinase C
–NF-
B pathway in primary peripheral T cells
1 Institute for Virology and Immunobiology, University of Würzburg, 97078 Würzburg, Germany 2 Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Correspondence to: T. Hünig; E-mail: huenig{at}vim.uni-wuerzburg.de
Transmitting editor: D. R. Littman
Mitogenic anti-CD28 antibody stimulates all peripheral T cells to proliferate in the absence of TCR ligation, providing an exception to the two-signal requirement of T cell responses. This antibody preferentially recognizes a mobilized signaling-competent form of CD28, normally induced following TCR ligation, thus providing a unique non-physiological tool to dissect CD28-specific signals leading to T cell proliferation. The protein kinase C (PKC)
–NF-
B pathway has recently been shown to integrate TCR- and CD28-derived signals in co-stimulation. We now demonstrate that this pathway is activated by mitogenic anti-CD28 antibody stimulation. In contrast to conventional anti-CD28 antibody, mitogenic anti-CD28 antibody induced activation of phospholipase C
and Ca2+ flux in peripheral rat T cells despite no or low levels of inducible tyrosine phosphorylation of TCR
chain, TCR-associated protein of 70 kDa (ZAP-70) or linker for activation of T cells (LAT)—critical components of the TCR signaling machinery. Nevertheless, PKC kinase activity in vitro was increased following mitogenic anti-CD28 antibody stimulation, as was membrane association of both PKC and Bcl10. As downstream targets of PKC activation, NF-B components translocated to the nucleus at levels comparable to those after TCR–CD28 co-stimulation. NF-B translocation was diminished by PKC inhibition, as was induction of the NF-B/AP-1 responsive activation marker CD69. We propose that co-stimulation is a sequential process in which appropriate TCR engagement is required to mobilize CD28 into a signaling-competent form which then activates the PKC–NF-B pathway necessary for IL-2 production and proliferation.
Keywords: CD28, co-stimulation, NF-B, protein kinase C
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