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Programmed Death (PD)-1:PD-Ligand 1/PD-Ligand 2 Pathway Inhibits T Cell Effector Functions during Human Tuberculosis¹

Javier O. Jurado^*,, Ivana B. Alvarez^*,, Virginia Pasquinelli^*,, Gustavo J. Martínez, María F. Quiroga^*,, Eduardo Abbate, Rosa M. Musella, H. Eduardo Chuluyan and Verónica E. García^2,*,

^* Department of Biological Chemistry, School of Sciences, University of Buenos Aires, Buenos Aires, Argentina; Laboratorio de Inmunogenética, Hospital de Clínicas José de San Martín, University of Buenos Aires, Buenos Aires, Argentina; and División de Tisioneumonología, Hospital F. J. Muñiz, Buenos Aires, Argentina

Protective immunity against Mycobacterium tuberculosis requires the generation of cell-mediated immunity. We investigated the expression and role of programmed death 1 (PD-1) and its ligands, molecules known to modulate T cell activation, in the regulation of IFN- production and lytic degranulation during human tuberculosis. We demonstrated that specific Ag-stimulation increased CD3⁺PD-1⁺ lymphocytes in peripheral blood and pleural fluid from tuberculosis patients in direct correlation with IFN- production from these individuals. Moreover, M. tuberculosis-induced IFN- participated in the up-regulation of PD-1 expression. Blockage of PD-1 or PD-1 and its ligands (PD-Ls: PD-L1, PD-L2) enhanced the specific degranulation of CD8⁺ T cells and the percentage of specific IFN--producing lymphocytes against the pathogen, demonstrating that the PD-1:PD-Ls pathway inhibits T cell effector functions during active M. tuberculosis infection. Furthermore, the simultaneous blockage of the inhibitory receptor PD-1 together with the activation of the costimulatory protein signaling lymphocytic activation molecule led to the promotion of protective IFN- responses to M. tuberculosis, even in patients with weak cell-mediated immunity against the bacteria. Together, we demonstrated that PD-1 interferes with T cell effector functions against M. tuberculosis, suggesting that PD-1 has a key regulatory role during the immune response of the host to the pathogen.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT; PICT 25996; to V.E.G.), National Council of Science and Technology (CONICET; PIP 5584; to V.E.G.), and the University of Buenos Aires (UBACyT M030; to V.E.G.). J.O.J. holds a fellowship from ANPCyT, Argentina. I.B.A. and V.P. are fellows of CONICET, Argentina. M.F.Q., H.E.C., and V.E.G. are members of the Researcher Career of CONICET, Argentina.

² Address correspondence and reprint requests to Dr. Verónica E. García, Department of Biological Chemistry, School of Sciences, University of Buenos Aires, Intendente Guiraldes 2160, Pabellón II, 4th floor, Capital Federal, 1428, Buenos Aires, Argentina. E-mail address: vgarcia{at}qb.fcen.uba.ar

³ Abbreviations used in this paper: SLAM, signaling lymphocytic activation molecule; PD-1, programmed death-1; PD-L, PD-1 ligand; CMI, cell-mediated immunity; HD, healthy donor; PB, peripheral blood; HR, high responder; LR, low responder; PF, pleural fluid; PFMC, PF mononuclear cell.