REGULATION OF IMMUNOSTIMULATORY FUNCTION AND COSTIMULATORY MOLECULE (B7-1 AND B7-2) EXPRESSION ON MURINE DENDRITIC CELLS

Dendritic cells (DC) play a critical role in the initiation of T cell- mediated immune responses, and express costimulatory molecules that ar e required for optimal activation of unprimed T cells. Studies on the regulation of the costimulatory molecules on DC have produced evidence from several systems that GM-CSF can up-regulate expression of CTLA4 counter receptor (CTLA4-CR) (but not intercellular adhesion molecule 1 (ICAM-1) and heat stable Ag (HsAg)) on DC. This is demonstrated on sp lenic DC, Langerhans cells, kidney DC in culture, and in a skin-explan t culture system, in which the increased expression of CTLA4-CR on Lan gerhans cells (LC) occurs concomitantly with their migration out of sk in. Interestingly, despite the ability of both CM-CSF and IFN-gamma in crease CTLA4-CR and maintain similar levels of ICAM-1, HsAg, and MHC m olecule expression, the functional consequences of these cytokines on splenic DC are distinctly different. GM-CSF enhances the ability of DC to stimulate both T cell proliferation and cytokine release, whereas IFN-gamma causes no increase in immunostimulatory function. Further an alysis of the CTLA4-CR on these cell populations by using the GL-1 and IG10 mAbs has shown that GM-CSF-cultured DC express high levels of bo th B7-1 and B7-2, whereas IFN-gamma-cultured DC express increased leve ls of only B7-2. These results suggest that optimal stimulation of unp rimed T cells to proliferate and release cytokines may require partici pation of both of these CTLA4 counter receptors, and confirm the impor tance of CM-CSF for the maturation of DC into potent stimulators of T cell activation.