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Inducible Costimulator: A Modulator of IFN- Production in Human Tuberculosis¹

María F. Quiroga^2,*,, Virginia Pasquinelli^2,*,, Gustavo J. Martínez^*,, Javier O. Jurado^*,, Liliana Castro Zorrilla, Rosa M. Musella, Eduardo Abbate, Peter A. Sieling^¶ and Verónica E. García^3,*,

^* Department of Microbiology, Parasitology and Immunology, Laboratorio de Inmunogenética, Hospital de Clínicas José de San Martín, Department of Immunology, "Instituto de Tisioneumonología Prof. Dr. Raúl Vaccarezza," University of Buenos Aires School of Medicine, and División Tisioneumonología, Hospital FJ Muñiz, Buenos Aires, Argentina; and ^¶ Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095

Effective host defense against Mycobacterium tuberculosis requires the induction of Th1 cytokine responses. We investigated the regulated expression and functional role of the inducible costimulator (ICOS), a receptor known to regulate Th cytokine production, in the context of human tuberculosis. Patients with active disease, classified as high responder (HR) or low responder (LR) patients according to their in vitro T cell responses against the Ag, were evaluated for T cell expression of ICOS after M. tuberculosis-stimulation. We found that ICOS expression significantly correlated with IFN- production by tuberculosis patients. ICOS expression levels were regulated in HR patients by Th cytokines: Th1 cytokines increased ICOS levels, whereas Th2-polarizing conditions down-regulated ICOS in these individuals. Besides, in human polarized Th cells, engagement of ICOS increased M. tuberculosis IFN- production with a magnitude proportional to ICOS levels on those cells. Moreover, ICOS ligation augmented Ag-specific secretion of the Th1 cytokine IFN- from responsive individuals. In contrast, neither Th1 nor Th2 cytokines dramatically affected ICOS levels on Ag-stimulated T cells from LR patients, and ICOS activation did not enhance IFN- production. However, simultaneous activation of ICOS and CD3 slightly augmented IFN- secretion by LR patients. Together, our data suggest that the regulation of ICOS expression depends primarily on the response of T cells from tuberculosis patients to the specific Ag. IFN- released by M. tuberculosis-specific T cells modulates ICOS levels, and accordingly, ICOS ligation induces IFN- secretion. Thus, ICOS activation may promote the induction of protective Th1 cytokine responses to intracellular bacterial pathogens.

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