CD28, IL-2-independent costimulatory pathways for CD8 T lymphocyte activation

We investigate, here, the mechanism of the costimulatory signals for CD8 T cell activation anal confirm that costimulation signals via CD28 do not app ear 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-a lpha can provide alternative costimulatory survival signals. IL-6 and TNF-a lpha costimulate naive CD8 T cells cultured on plate-bound anti-CD3 in the absence of CD28 ligation, They act directly on sorted CDS-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-alpha provide costimulation to na ive CD8 T cells from CD28, IL-2, or IL-2R alpha-deficient mice, and thus fu nction in the absence of the B7-CD28 and IL-2 costimulatory pathways. The C D8 T cell generated via the anti-CD3 plus IL-6 and TNF-alpha pathway have e ffector function in that they express strong cytolytic activity on Ag-speci fic targets; They secrete only very small amounts of any of the cytokines t ested 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-alpha provides a novel pathway that can substitute for signals from CD4 helper cells or professional APC, This may be significant in the respo nse to viral Ags, which can be potentially expressed on the surface of any class I MHC-expressing cell.