A Role for CD40-CD40 Ligand Interactions in the Generation of Type 1 Cytokine Responses in Human Leprosy

• Published in: The Journal of immunology (1950) Vol. 165; no. 3; pp. 1506 - 1512
• Main Authors: Yamauchi, Paul S, Bleharski, Joshua R, Uyemura, Koichi, Kim, Jenny, Sieling, Peter A, Miller, Ari, Brightbill, Hans, Schlienger, Katia, Rea, Thomas H, Modlin, Robert L
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.08.2000
• Subjects: AIDS/HIV; CD40 antigen; CD40 Antigens - biosynthesis; CD40 Antigens - genetics; CD40 Antigens - metabolism; CD40 Antigens - physiology; CD40 Ligand; CD40L protein; Cell Membrane - genetics; Cell Membrane - immunology; Cell Membrane - metabolism; Cells, Cultured; Cytokines - biosynthesis; g-Interferon; Humans; Immunity, Cellular; Interleukin-12 - biosynthesis; Leprosy, Lepromatous - immunology; Leprosy, Lepromatous - metabolism; Leprosy, Lepromatous - pathology; Leprosy, Tuberculoid - immunology; Leprosy, Tuberculoid - metabolism; Leprosy, Tuberculoid - pathology; Ligands; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Monocytes - immunology; Monocytes - metabolism; Mycobacterium leprae; Mycobacterium leprae - immunology; RNA, Messenger - biosynthesis; Th1 Cells - immunology; Th1 Cells - metabolism; Up-Regulation - genetics; Up-Regulation - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.3.1506

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 production of IL-12, an obligate signal for generation of Th1 cytokine responses. The expression and interaction of CD40 and CD40L were investigated in human infectious disease using leprosy as a model. CD40 and CD40L mRNA and surface protein expression were predominant in skin lesions of resistant tuberculoid patients compared with the highly susceptible lepromatous group. IL-12 release from PBMC of tuberculoid patients stimulated with Mycobacterium leprae was partially inhibited by mAbs to CD40 or CD40L, correlating with Ag-induced 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 monocyte APC resulted in CD40L-CD40-dependent production of IL-12. In contrast, 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. leprae. Furthermore, IL-10, a cytokine predominant in lepromatous lesions, blocked the IFN-gamma up-regulation of CD40 on monocytes. These data suggest that 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 lepromatous leprosy, probably participates in the cell-mediated immune response to microbial pathogens.