No abstract

Visceral leishmaniasis (VL) is a disseminated and lethal disease of reticulo-endothelial system caused by protozoan parasites Leishmania donovani and L. infantum, which are known to induce host T cell suppression. To understand the impact of parasite load on T cell function, the present was focused on parasite load with T cell function in bone marrow of 26 VL patients. We observed significant enrichment of forkhead box protein 3 (FoxP3) (P = 0·0003) and interleukin (IL)-10 FoxP3 regulatory T cells (T ) (P = 0·004) in the bone marrow (BM) of patients with high parasite load (HPL) compared with low parasite load (LPL). Concordantly, T effector cells producing interferon (IFN)-γ (P = 0·005) and IL-17A (P = 0·002) were reduced in the BM of HPL. Blocking of T -cell derived suppressive cytokines [(IL-10 and transforming growth factor (TGF)-β] rescued the effector T cells and their functions. However, it was observed that TGF-β levels were dominant, favouring T cell differentiation. Furthermore, the low ratio of IL-6/TGF-β favours the suppressive milieu in HPL patients. Here we show the change in levels of various cytokines with the parasitic load during active VL, which could be helpful in devising newer immunotherapeutic strategies against this disease.

Prolonged therapy, drug toxicity, noncompliance, immune suppression, and alarming emergence of drug resistance necessitate the search for therapeutic vaccine strategies for tuberculosis (TB). Such strategies ought to elicit not only IFN-γ, but polyfunctional response including TNF-α, which is essential for protective granuloma formation. Here, we investigated the impact of PD-1 inhibition in facilitating protective polyfunctional T cells (PFTs), bacillary clearance, and disease resolution. We have observed PD-1 inhibition preferentially rescued the suppressed PFTs in active tuberculosis patients. In addition, polyfunctional cytokine milieu favored apoptosis of infected MDMs over necrosis with markedly reduced bacillary growth ( CFU) in our in vitro monocyte-derived macrophages (MDMs) infection model. Furthermore, the animal study revealed a significant decline in the bacterial burden in the lungs and spleen of infected mice after in vivo administration of α-PD-1 along with antitubercular treatment. Our findings suggest that rescuing polyfunctional immune response by PD-1 inhibition works synergistically with antituberculosis chemotherapy to confer improved control over bacillary growth and dissemination. In summary, our data strongly indicate the therapeutic potential of α-PD-1 as adjunct immunotherapy that can rejuvenate suppressed host immunity and enhance the efficacy of candidate therapeutic vaccine(s). Keywords: polyfunctional T cells r PD-1 r Treg cells r tuberculosis r immunotherapyAdditional supporting information may be found online in the Supporting Information section at the end of the article. Abbreviations: MDM: monocyte-derived macrophage · M.tb: Mycobacterium tuberculosis · PFT: polyfunctional T cell · TB: tuberculosis