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Departments of
*
Immunology and
Microbiology, University of Washington, Seattle, WA 98195
CD28 is a major T cell costimulatory molecule, delivering signals
distinct from those of the CD3/TCR complex, which regulate cytokine and
cytokine receptor expression, cell proliferation, and cell viability.
CD28 needs to be cross-linked to initiate signals, yet both of its
ligands, CD80 and CD86, are expressed as monomers. Previously, we
determined the cytoplasmic tail of CD80 is required for CD28-mediated
costimulation and subcellular relocalization of CD80 in lymphocytes. In
this study, we report that Reh B cell transfectants expressing CD80
with mutations in the cytoplasmic tail region either at 275–278
(RRNE
AAAA, CD80/4A) or serine 284 (SA, CD80/SA) can bind ligand
similar to transfectants expressing wild-type CD80, yet are unable to
costimulate T cell proliferation. These mutant CD80 molecules are
expressed on the surface of the Reh cells in small clusters or foci
indistinguishable from those of wild-type CD80 molecules. However,
mutant CD80 molecules unlike wild-type CD80 cannot be readily induced
by ligand into caps. Thus, small clusters of CD80 found on APC are
insufficient to initiate CD28-mediated signals, and the formation of
CD80 caps appears to be a critical factor regulating the initiation of
T cell costimulation. A 30-kDa phosphoprotein that associates with the
cytoplasmic tail of CD80 in activated cells may play a role in CD80
redistribution and thus CD28-mediated costimulation. These results
indicate two distinct regions of the CD80 cytoplasmic tail regulate its
costimulatory function, and both regions are required for CD80
function.
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