PURPOSE: Elicitation of optimal effector T cell response requires a balance between co-stimulatory (CD28, CD134 and CD137 etc.) and co-inhibitory signals (CTLA-4 and PD-1/CD279). The importance of co-inhibitory signal lies in dampening of T cell response aimed at preventing bystander tissue damage during waning phase of immunity. However, aberrant or excessive inhibition may result in deficiency of host immunity following M.tuberculosis (Mtb.) infection, thus resulting in the development of disseminated form of disease like miliary tuberculosis (MTB). Recently, programmed death-1 (PD-1) receptor and its ligands, PD-L1/PD-L2, have been shown to dampen host immunity in the setting of chronic viral and bacterial infections.
METHODS: In the present study, we examined the expression and function of PD-1 and its ligands on the host immunity among tuberculosis patients involving multicolor Flow Cytometry and in-vitro cell culture techniques.
RESULTS: PD-1+ T cells of bronchiolar lavage are 2 fold higher than the peripheral PD-1+T cells of MTB (p<0.0002, n=13) and pulmonary TB (p<0.0011, n=53) and 4 fold higher than that of Healthy Controls (p<0.0001, n=23). Furthermore, we also observed significantly higher frequencies of PD-1 ligands (PD-L1 and PD-L2) positive T cells, B (CD19+) cells and monocytes (CD14+). Antibody blocking of PD-1 increased Mtb. specific IFN-γ and IL-2 production by T cells, suggesting important role of PD-1/PD-L pathway in dampening the host immunity to Mtb. infection at the pathologic site of MTB.
CONCLUSIONS: Locally accumulated T cells were dominantly PD-1+/PD-L1+ and blockade of this pathways (PD-1-PD-L1) can restored the host protective immunity.
CLINICAL IMPLICATIONS: Our results suggest that PD-1-PD-L1/L2 pathway provides a novel approach to manipulate the host T cell response in chronic intracellular infections like M.tuerculosis. Further study to unravel the mechanistic regulation of the PD-1-PD-L1/L2 pathway relating to the effector T cell function may constitute molecular strategies for rescuing protective immunity in human tuberculosis.
DISCLOSURE: The following authors have nothing to disclose: Dipendra Mitra, Amar Singh, Aparajita Bindu Dey, Anant Mohan
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