CD44 plays a co-stimulatory role in murine T cell activation: ligation of CD44 selectively co-stimulates IL-2 production, but not proliferation in TCR-stimulated murine Th1 cells

The murine CD44 receptor family is thought to be involved ina variety of lymphocyte functions, including lymphopoesis, lymphocytehoming and cell migration. Herein, we show that murine CD44also plays a role as a co-stimulatory molecule for the activationof CD4⁺ T cells. Ligation of CD44 by mAb enhanced IL-2 productionof long-term cultured, anti-CD3-stimulated T_h1 cell lines. Moreover,anti-CD44 mAb synergized with anti-CD28 mAb in exerting thiseffect. A synergism of anti-CD28 and anti-CD44 mAb to co-stimulateIL-2 production was also observed in anti-CD3- triggered, freshlyisolated splenic CD4⁺ T cells. Blocking experiments with cyclosporinA indicated that the intracellular pathways used by the CD28and CD44 molecules appear to be different. In contrast to theeffects on the IL-2 production of T_h1 cells, neither anti-CD44mAb alone nor the combination of anti-CD44 with anti-CD28 wereable to induce proliferation of anti-CD3-triggered T_h1 cells.In accordance, triggering of CD44 and/or CD28 by mAb was notsufficient to reverse the previously described ‘proliferativeblock’. This term describes the unresponsiveness of T_h1cells against IL-2, which occurs when T_h1 cells are triggeredby anti-CD3 in the absence of co-signals. These data lead usto propose a model of T_h1 cell activation which includes twofunctionally different types of co-signals: one for IL-2 productionand a separate one for proliferation.