Experimental pulmonary tuberculosis and immune inhibitory signals: A potential role for PD1-PD1-ligand interplay

Immune responses may substantially differ between conventional laboratory antigens and microbial ones. Pathogens like Mycobacterium tuberculosis (Mtb) have evolved complex mechanisms to evade, divert or subvert immune responses. Tuberculosis (TB) is a major cause of death worldwide whose etiology, M. tuberculosis, produces latent asymptomatic infections and chronic progressive diseases, being pulmonary TB its most important manifestation. TB immunity is mediated by Th1-type responses, nevertheless this response seems not enough to definitely eradicate the chronic infection, nor the latent bacilli. The experimental pulmonary tuberculosis is a convenient in vivo model to study the disease because it provides important advantages. Mice infection is established through the airways and murine immune responses are well known. Different aspects of the disease can be explored using different mice strains with different susceptibilities. Another crucial advantage is the suitability to infect with different mycobacterial strains, including clinical isolates and mutant bacteria. Mycobacteria induce strong Th1-type responses, however, infected immunocompetent hosts are somehow rendered unable to generate effective sterilizing immunity and bacilli can persist long periods in an ill-understood dormant state. Although the molecule Programmed Death-1 (PD1) belongs to the CD28 co-stimulatory family, unlike CD28, PD1 is an inhibitory receptor inducible upon activation of T, B and NKT cells, with two ligands described (PDL-1/PDL-2). The relevance of the PD1/PDL-1 pathway to induce and maintain immunologic tolerance is well documented, and dysfunction in this pathway is associated with autoimmunity. Recently, the PD1/PDL-1 pathway was shown as a suitable target for exploitation by chronic viral diseases provoking T cell exhaustion (a phenotype that can be reverted in vivo by blocking the PD1/PDL1 interaction). It is thus possible that other chronic infectious agents may use this strategy too. We therefore evaluated the in vivo PD1 expression on CD4+ and CD8+ T cells, both in the TB target organ, the lung, and the mediastinal lymph nodes, along the infection (days 1-60) in Balb/c mice. Results revealed that compared to the less virulent M. canetti, airborne infection with the virulent strain M. tuberculosis H37Rv, triggered an increase in PD1+ T cells, especially in the lungs, although with different kinetics for CD4+ and CD8+ lymphocytes. Conceivably, virulent Mtb might elicit this inhibitory molecule in effector T cells to facilitate both the establishing and the persistence of the infection.