TCR-INDEPENDENT ACTIVATION OF HUMAN CD4(-) T-CELLS BY ANTI-CD28 PLUS IL-2 - INDUCTION OF CLONAL EXPANSION AND PRIMING FOR A TH2 PHENOTYPE()45RO()

In this study we show that uncommitted human CD4(+) CD45RA(+)RO(-)CD25 (-)CD71(-) HLA-DR(-) T cells can be primed for a Th2 phenotype before they encounter TCR signals and before they are exposed to IL-4. We fou nd that >99% of uncommitted T cells proliferated upon costimulation by immobilized anti-CDS plus anti-CD28 mAbs and differentiated into pure Th1 cells. In contrast, uncommitted T cells did not respond to stimul ation by either anti-CD3 or anti-CD28, or by IL-2 alone, Interestingly , 5% of uncommitted T cells proliferated efficiently in response to st imulation by immobilized anti-CD28 plus IL-2 (in the absence of TCR/CD 3 signals) and differentiated into pure Th2 ''precursor'' cells, Like murine CD4(+) NK1.1(+) T cells, human Th2 precursors promptly expresse d mRNA for Th2 cytokines upon stimulation via the TCR/CD3 complex by a nti-CD3 mAb or by staphylococcal enterotoxin B, and secreted up to 50 ng of IL-4, IL-5, and IL-13 per 10(6) cells, Th2 ''precursors'' develo ped only in the complete absence of IL-4, as addition of 0.1 U (5 pg) of exogenous IL-4 suppressed their clonal expansion by >90%, whereas a ddition of neutralizing anti-IL-4 mAb had no effect, Together these re sults suggest that, in vivo, a significant fraction of uncommitted T c ells may be primed for a Th2 phenotype independent of Ag and IL-4 if t hey are exposed to Th1 cell-derived IL-2 and simultaneously interact w ith accessory cells bearing the natural CD28 ligands B7-1 and B7-2. Wh en stimulated by specific Ag, such primed Th2 precursor cells may prov ide a source of IL-4 to promote Th2 immunity.