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Signaling Lymphocytic Activation Molecule Expression and Regulation in Human Intracellular Infection Correlate with Th1 Cytokine Patterns¹

Verónica E. García^*,, María F. Quiroga^*,, María T. Ochoa, Laura Ochoa^*, Virginia Pasquinelli^*,, Leonardo Fainboim^*,, Liliana M. Olivares^||, Raúl Valdez, Daniel O. Sordelli^*, Gregorio Aversa^#, Robert L. Modlin^,¶ and Peter A. Sieling^2,

^* Department of Microbiology, Parasitology, and Immunology, University of Buenos Aires School of Medicine, Buenos Aires, Argentina; Laboratorio de Inmunogenética and Division of Dermatology, Hospital de Clínicas José de San Martín, University of Buenos Aires, Buenos Aires, Argentina; Division of Dermatology and ^¶ Department of Microbiology and Immunology, University of California, Los Angeles, Medical School, Los Angeles, CA 90095; ^|| Division of Dermatology, Leprosy Section, Hospital de Infecciosas F.J. Muñiz, Buenos Aires, Argentina; and ^# Autoimmune Diseases Unit, Novartis Forschungsinstitut, Vienna, Austria

Induction of Th1 cytokines, those associated with cell-mediated immunity, is critical for host defense against infection by intracellular pathogens, including mycobacteria. Signaling lymphocytic activation molecule (SLAM, CD150) is a transmembrane protein expressed on lymphocytes that promotes T cell proliferation and IFN- production. The expression and role of SLAM in human infectious disease were investigated using leprosy as a model. We found that SLAM mRNA and protein were more strongly expressed in skin lesions of tuberculoid patients, those with measurable CMI to the pathogen, Mycobacterium leprae, compared with lepromatous patients, who have weak CMI against M. leprae. Peripheral blood T cells from tuberculoid patients showed a striking increase in the level of SLAM expression after stimulation with M. leprae, whereas the expression of SLAM on T cells from lepromatous patients show little change by M. leprae stimulation. Engagement of SLAM by an agonistic mAb up-regulated IFN- production from tuberculoid patients and slightly increased the levels of IFN- in lepromatous patients. In addition, IFN- augmented SLAM expression on M. leprae-stimulated peripheral blood T cells from leprosy patients. Signaling through SLAM after IFN- treatment of Ag-stimulated cells enhanced IFN- production in lepromatous patients to the levels of tuberculoid patients. Our data suggest that the local release of IFN- by M. leprae-activated T cells in tuberculoid leprosy lesions leads to up-regulation of SLAM expression. Ligation of SLAM augments IFN- production in the local microenvironment, creating a positive feedback loop. Failure of T cells from lepromatous leprosy patients to produce IFN- in response to M. leprae contributes to reduced expression of SLAM. Therefore, the activation of SLAM may promote the cell-mediated immune response to intracellular bacterial pathogens.

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