Signaling lymphocytic activation molecule expression and regulation in human intracellular infection correlate with Th1 cytokine patterns

Induction of Th1 cytokines, those associated with cell-mediated immunity, i s critical for host defense against infection by intracellular pathogens, i ncluding mycobacteria. Signaling lymphocytic activation molecule (SLAM, CD1 50) is a transmembrane protein expressed on lymphocytes that promotes T cel l proliferation and IFN-gamma production. The expression and role of SLAM i n human infectious disease were investigated using leprosy as a model. We f ound that SLAM mRNA and protein were more strongly expressed in skin lesion s of tuberculoid patients, those with measurable CMI to the pathogen, Mycob acterium leprae, compared with lepromatous patients, who have weak CMI agai nst M. leprae. Peripheral blood T cells from tuberculoid patients showed a striking increase in the level of SLA-M expression after stimulation with M . leprae, whereas the expression of SLAM on T cells from lepromatous patien ts show little change by M. leprae stimulation. Engagement of SLAM by an ag onistic mAb up-regulated IFN-gamma production from tuberculoid patients and slightly increased the levels of IFN-gamma in lepromatous patients. In add ition, IFN-gamma augmented SLAM expression on Al. leprae-stimulated periphe ral blood T cells from leprosy patients. Signaling through SLAM after IFN-g amma treatment of Ag-stimulated cells enhanced IFN-gamma production in lepr omatous patients to the levels of tuberculoid patients. Our data suggest th at the local release of IFN-gamma by M. leprae-activated T cells in tubercu loid leprosy lesions leads to up-regulation of SLAM expression. Ligation of SLAM augments IFN-gamma production in the local microenvironment, creating a positive feedback loop. Failure of T cells from lepromatous leprosy pati ents to produce IFN-gamma in response to M. leprae contributes to reduced e xpression of SLAM. Therefore, the activation of SLAM may promote the cell-m ediated immune response to intracellular bacterial pathogens.