Inhibiting PD-1 Restores Poly-Functional T Cell Response in Tuberculosis and Synergizes with Chemotherapy

Background: Prolonged anti-tubercular therapy associated with toxicity, non-compliance, immune suppression and alarming emergence of drug resistance necessitates the search for therapeutic vaccine strategies for tuberculosis (TB). Such strategies ought to elicit not only IFN-?, but poly-functional response including TNF-a, which is essential for protective granuloma formation. Here, we investigated the impact of PD-1 inhibition in facilitating protective poly-functional T cells (PFTs), bacillary clearance and disease resolution. The objectives were to i) determine the PFTs profile in active tuberculosis patients as compared to latent (PPD ) tuberculosis patients and healthy controls (PPD-), ii) understand the role of PD-1 pathway and Treg cells in the suppression of protective PFTs response and iii) validate the efficacy of a-PD-1 in vitro and in vivo in rescuing protective PFTs and disease resolution. Methods: Flow cytometry, real-time polymerase chain reaction, western blotting, in vitro monocyte derived macrophages (MDMs) infection studies, and in vivo mice infection studies. Findings: We observed reduced PFTs response in TB patients and their preferential rescue by blocking PD-1 due to higher expression of PD-1 on them. PFTs favored the apoptotic death of infected MDMs over necrosis and showed markedly reduced bacillary growth in MDMs. Animal study revealed significant decline in the bacterial burden in lungs and spleen of infected mice after in vivo administration of a-PD-1 in combination with anti-tubercular treatment. Interpretation: Our data strongly indicates the therapeutic potential of a-PD-1 as an adjunct immunotherapy which can rejuvenate suppressed host immunity and potentially improve drug potency of candidate therapeutic vaccine(s). Funding: Supported by Indian Council of Medical Research (ICMR) and Department of Biotechnology (DBT), Government of India. Declaration of Interest: The authors declare no competing financial interests. Ethical Approval: The study was approved by Institutional Ethics Committee.