Tim-3 blocking rescue macrophage and T cell function against Mycobacterium tuberculosis infection in HIV+ patients

Introduction : T cell immunoglobulin and mucin domain (Tim) 3 and programmed death 1 (PD-1) are co-inhibitory receptors involved in the so-called T cell exhaustion, and in vivo blockade of these molecules restores T cell dysfunction. High expression of Tim-3 and PD-1 is induced after chronic antigen-specific stimulation of T cells during HIV infection. We have previously demonstrated that the interaction of Tim-3 with its ligand galectin-9 induces macrophage activation and killing of Mycobacterium tuberculosis. Our aim in this study was to analyze the Tim-3 expression profile before and after six months of antiretroviral therapy and the impact of Tim-3 and PD-1 blocking on immunity against M. tuberculosis. Materials and methods : HIV+ patients naive to anti-retroviral therapy (ART) were followed up for six months. Peripheral immune-cell phenotype (CD38/HLA-DR/galectin-9/Tim-3 and PD-1) was assessed by flow cytometry. Supernatants were analyzed with a multiplex cytokine detection system (human Th1/Th2 cytokine Cytometric Bead Array) by flow cytometry. Control of bacterial growth was evaluated by using an in vitro experimental model in which virulent M. tuberculosis -infected macrophages were cultured with T cells in the presence or absence of Tim-3 and PD-1 blocking antibodies. Interleukin-1 beta treatment of infected macrophages was evaluated by enumerating colony-forming units. Results : We showed that HIV+ patients had an increased expression of Tim-3 in T cells and were able to control bacterial growth before ART administration. By blocking Tim-3 and PD-1, macrophages and T cells recovered their functionality and had a higher ability to control bacterial growth; this result was partially dependent on the restitution of cytokine production. Conclusions : In this study, we demonstrated that increased Tim-3 expression can limit the ability of the immune system to control the infection of intracellular bacteria such as M. tuberculosis . The use of ART and the in vitro manipulation of the Tim-3 and PD-1 molecules restored the functionality of T cells and macrophages to restrict bacterial growth. Our results provide a novel immune strategy that may be implemented in the near future in order to improve the immune responses in HIV+ patients. Keywords: HIV; tuberculosis; Tim-3; galectin 9; PD-1. (Published: 19 October 2015) Citation: Sada-Ovalle I et al. Journal of the International AIDS Society 2015, 18 :20078 http://www.jiasociety.org/index.php/jias/article/view/20078 | http://dx.doi.org/10.7448/IAS.18.1.20078