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J Biol Chem, Vol. 274, Issue 5, 3116-3124, January 29, 1999
From the Ligation of either CD80 (B7-1) or CD86 (B7-2),
two principal ligands for CD28, is thought to skew the immune response
toward Th1 or Th2 differentiation. We have examined early signal
transduction pathways recruited following T cell stimulation with
either CD80 or CD86. Purified human peripheral T cells or Jurkat T
cells were stimulated with Chinese hamster ovary (CHO) cells expressing
either human CD80 (CHO-CD80) or human CD86 (CHO-CD86) or with anti-CD28 monoclonal antibody (mAb). In the presence of phorbol 12-myristate 13-acetate, both CHO-CD80 and CHO-CD86, like anti-CD28 mAb, were capable of stimulating cytokine production from both human peripheral T
cells and Jurkat T cells. Both CHO-CD80 and CHO-CD86, in the presence
of anti-CD3 mAb, costimulated NFAT-dependent
transcriptional activation. Several intracellular signaling proteins,
such as CBL and VAV, were phosphorylated on tyrosine in response to
CD80, CD86, and anti-CD28 mAb. Surprisingly, although stimulation of Jurkat T cells with either CHO-CD80 or anti-CD28 mAb resulted in robust
tyrosine phosphorylation of CD28 itself, ligation with CHO-CD86 was
unable to induce detectable CD28 tyrosyl phosphorylation over a range
of stimulation conditions. In addition, the association of
phosphoinositide 3-kinase with CD28 and enhanced tyrosine
phosphorylation of phospholipase C
CD80 and CD86 Are Not Equivalent in Their Ability to Induce the
Tyrosine Phosphorylation of CD28
,
§, and
¶
Department of Pediatric Oncology,
were seen after anti-CD28 mAb and
CHO-CD80 stimulation but to a much lesser extent after CHO-CD86
stimulation. Thus, ligation of CD28 with either CD80 or CD86 leads to
shared early signal transduction events such as the tyrosine
phosphorylation of CBL and VAV, to NFAT-mediated transcriptional
activation, and to the costimulation of interleukin-2 and
granulocyte-macrophage colony-stimulating factor production. However,
CD80 and CD86 also induce distinct signal transduction pathways
including the tyrosine phosphorylation of CD28 and phospholipase C
1
and the SH2-dependent association of phosphoinositide
3-kinase with CD28. These quantitative, if not qualitative, differences
between signaling initiated by these two ligands for CD28 may
contribute to functional differences (e.g. Th1 or Th2
differentiation) in T cell responses.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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