ACQUISITION OF INTERLEUKIN-5 SECRETION BY HUMAN NAIVE T-HELPER CELLS IS REGULATED BY DISTINCT SIGNALS FROM BOTH THE T-CELL RECEPTOR CD3 COMPLEX AND CD2

We developed a human naive T-helper (Th) cell differentiation model wi th anti-CD3 monoclonal antibody (MoAb), using a B-cell line as source of costimulation. In this system, we examined the contribution of the T-cell receptor (TCR)/CD3-derived signals and that of lymphocyte funct ion-associated antigen-1 (LFA-1) and CD2 in regulating Th-cell subset differentiation. We found that lowering the level of anti-CD3 MoAb dec reased tumour necrosis factor-alpha (TNF-alpha) production, while incr easing secretion of the Th2 cytokines, interleukin-5 (IL-5) and interl eukin-13 (IL-13). Secretion of interferon-gamma (IFN-gamma) was not in fluenced by the strength of the anti-CD3 signal. Under conditions wher e Th0 cells are generated, co-culture with anti-CD2 F(ab')(2) MoAb led to the generation of Th cells that secreted 30-35% less IL-5, while n ot affecting secretion of IFN-gamma or granulocyte-macrophage colony-s timulating factor (GM-CSF). By contrast, anti-CD18 MoAb F(ab')(2) inhi bited IFN-gamma and GM-CSF levels only in the primary stimulation, but did not affect cytokine levels after restimulation. Neither anti-CD2 nor anti-CD18 F(ab')(2) MoAbs could alter cytokine secretion profiles of peripheral blood-derived memory/effector Th cells. Our results indi cate that acquisition of IL-5 secretion capability by Th cells is regu lated mainly by signals transduced by the TCR/CD3 complex and by the p resence of interleukin-4 (IL-4), while the CD2/LFA-3 pathway plays an additional, but minor, role. These regulatory CD2-derived signals, how ever, are distinct from those generated by the TCR/CD3 complex.