CD40 LIGATION OF HUMAN KERATINOCYTES INHIBITS THEIR PROLIFERATION ANDINDUCES THEIR DIFFERENTIATION

While CD40-CD40 ligand interactions are known to regulate B cell proli feration and differentiation, much less is known about the role this r eceptor plays on other cell types, especially those of nonhemopoietic origin. We report here that CD40 is expressed in normal human epidermi s in situ, especially on the basal cell layer, and that it is maintain ed on cultured epidermal basal cells, Immunoprecipitation and SDS-PAGE analysis confirms that CD40 expressed by epidermal basal cells is imm unologically related to the B cell CD40. IFN-gamma up-regulates CD40 e xpression on cultured keratinocytes, whereas other proinflammatory cyt okines, such as IL-1 or TNF-alpha, have little effects, Using CD40-lig and-transfected L cells (CD40Lc), we demonstrated that CD40 triggering results in an enhanced secretion of both IL-8 and TNF-alpha by cultur ed epidermal basal cells, suggesting that CD40-CD40L interactions may play a role in amplifying the cutaneous inflammatory reactions, More i mportantly, we found that keratinocyte proliferation was significantly inhibited when the cells were grown on CD40Lc, as compared with CD32- transfected, or nontransfected, L cells. This inhibitory effect can be reversed substantially by pretreatment of keratinocytes with anti-CD4 0 mAb. In addition, inhibition of proliferation could be obtained by a dding a soluble form of CD40 ligand to the keratinocyte cultures. Inte restingly, inhibition of keratinocyte proliferation on CD40Lc correlat es with differentiation of the cells, as assessed by morphologic analy sis and increased profilaggrin content. Collectively, these results de monstrate that CD40 is expressed and functional on human epidermal bas al cells and that, on these cells, CD40 ligation may be a signal for l imitation of cell growth and induction of differentiation.