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Activation of Signaling Lymphocytic Activation Molecule Triggers a Signaling Cascade That Enhances Th1 Responses in Human Intracellular Infection¹

María F. Quiroga^*,, Gustavo J. Martínez^*,, Virginia Pasquinelli^*,, Mónica A. Costas, María M. Bracco, Alejandro Malbrán^¶, Liliana M. Olivares^||, Peter A. Sieling^# and Verónica E. García^2,*,

^* Department of Microbiology, Parasitology, and Immunology, University of Buenos Aires School of Medicine, Buenos Aires, Argentina; Laboratorio de Inmunogenética, Hospital de Clínicas José de San Martín, and Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas A. Lanari, University of Buenos Aires, Buenos Aires, Argentina; Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina; ^¶ Departamento de Alergia e Inmunología, Hospital Británico, Buenos Aires, Argentina; ^|| Division of Dermatology, Leprosy Section, Hospital de Infecciosas F. J. Muñiz, Buenos Aires, Argentina; and ^# Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

T cell production of IFN- contributes to host defense against infection by intracellular pathogens, including mycobacteria. Lepromatous leprosy, the disseminated form of infection caused by Mycobacterium leprae, is characterized by loss of cellular response against the pathogen and diminished Th1 cytokine production. Relieving bacterial burden in Ag-unresponsive patients might be achieved through alternative receptors that stimulate IFN- production. We have previously shown that ligation of signaling lymphocytic activation molecule (SLAM) enhances IFN- in mycobacterial infection; therefore, we investigated molecular pathways leading from SLAM activation to IFN- production in human leprosy. The expression of the SLAM-associated protein (an inhibitory factor for IFN- induction) on M. leprae-stimulated cells from leprosy patients was inversely correlated to IFN- production. However, SLAM ligation or exposure of cells from lepromatous patients to a proinflammatory microenvironment down-regulated SLAM-associated protein expression. Moreover, SLAM activation induced a sequence of signaling proteins, including activation of the NF-B complex, phosphorylation of Stat1, and induction of T-bet expression, resulting in the promotion of IFN- production, a pathway that remains quiescent in response to Ag in lepromatous patients. Therefore, our findings reveal a cascade of molecular events during signaling through SLAM in leprosy that cooperate to induce IFN- production and strongly suggest that SLAM might be a focal point for therapeutic modulation of T cell cytokine responses in diseases characterized by dysfunctional Th2 responses.

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