A role for CD40-CD40 ligand interactions in the generation of type 1 cytokine responses in human leprosy

The interaction of CD40 ligand (CD40L) expressed by activated T cells with CD40 on macrophages has been shown to be a potent stimulus for the producti on of IL-12, an obligate signal for generation of Th1 cytokine responses. T he expression and interaction of CD40 and CD40L were investigated in human infectious disease using leprosy as a model. CD40 and CD40L mRNA and surfac e protein expression were predominant in skin lesions of resistant tubercul oid patients compared with the highly susceptible lepromatous group. IL-12 release from PBMC of tuberculoid patients stimulated with Mycobacterium lep rae was partially inhibited by mAbs to CD40 or CD40L, correlating with Ag-i nduced up-regulation of CD40L on T cells. Cognate recognition of M, leprae Ag by a T cell clone derived from a tuberculoid lesion in the context of mo nocyte APC resulted in CD40L-CD40-dependent production of IL-12, In contras t, M, leprae-induced IL-12 production by PBMC from lepromatous patients was not dependent on CD40L-CD40 ligation, nor was CD40L up-regulated by M. lep rae. Furthermore, IL-10, a cytokine predominant in lepromatous lesions, blo cked the IFN-gamma up-regulation of CD40 on monocytes, These data suggest t hat T cell activation in situ by M, leprae in tuberculoid leprosy leads to local up-regulation of CD40L, which stimulates CD40-dependent induction of IL-12 in monocytes. The CD40-CD40L interaction, which is not evident in lep romatous leprosy, probably participates in the cell-mediated immune respons e to microbial pathogens.