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*
Molecular Pathology Program, University of California at San Diego, La Jolla, CA 92093; and
Trudeau Institute, Saranac Lake, NY 12983
We investigate, here, the mechanism of the costimulatory signals
for CD8 T cell activation and confirm that costimulation signals via
CD28 do not appear to be required to initiate proliferation, but
provide survival signals for CD8 T cells activated by TCR ligation. We
show also that IL-6 and TNF-
can provide alternative costimulatory
survival signals. IL-6 and TNF- costimulate naive CD8 T cells
cultured on plate-bound anti-CD3 in the absence of CD28 ligation.
They act directly on sorted CD8-positive T cells. They also costimulate
naive CD8 T cells from Rag-2-deficient mice, bearing transgenic TCRs
for HY, which lack memory cells, a potential source of IL-2 secretion
upon activation. IL-6 and TNF- provide costimulation to naive CD8 T
cells from CD28, IL-2, or IL-2R-deficient mice, and thus function in
the absence of the B7-CD28 and IL-2 costimulatory pathways. The CD8 T
cell generated via the anti-CD3 plus IL-6 and TNF- pathway have
effector function in that they express strong cytolytic activity on
Ag-specific targets. They secrete only very small amounts of any of the
cytokines tested upon restimulation with peptide-loaded APC. The
ability of the naive CD8 T cells to respond to TCR ligation and
costimulatory signals from IL-6 and TNF- provides a novel pathway
that can substitute for signals from CD4 helper cells or professional
APC. This may be significant in the response to viral Ags, which can be
potentially expressed on the surface of any class I MHC-expressing
cell.
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