Inhibiting the programmed death 1 pathway rescues Mycobacterium tuberculosis-specific interferon γ-producing T cells from apoptosis in patients with pulmonary tuberculosis

Amar Singh, Anant Mohan, Aparajit B. Dey, Dipendra K. Mitra

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

Abstract

Background. Overexpression of programmed death 1 (PD-1) receptor is thought to inhibit the effector T-cell response in human tuberculosis. However, the precise mechanism of such inhibition remains unclear. The present study addresses the role of PD-1 in dampening host T-cell function among patients with pulmonary tuberculosis. Methods. Expression of PD-1 and its ligands (PD-L1/L2) on T cells, B cells, and monocytes was evaluated by flow cytometry (FACS). In vitro stimulation of peripheral blood mononuclear cells in the presence of Mycobacterium tuberculosis antigens was performed with and without blocking PD-1, and intracellular cytokine production was measured by FACS. Results. We showed higher frequencies of T cells, monocytes, and B cells expressing PD-1 and its ligand(s) among patients with pulmonary tuberculosis. Infections with live M. tuberculosis upregulated PD-L1 expression on monocytes. In vitro PD-1 blocking rescued M. tuberculosis-specific interferon γ (IFN-γ)-producing T cells from undergoing apoptosis. The number of PD-1-expressing T cells decreased significantly during therapy and inversely correlated with IFN-γ-dominant T-cell response against M. tuberculosis. Conclusions. Manipulation of PD-1 signaling may restore the host T-cell response and thus may have therapeutic potential. PD-1 also may serve as a biomarker to monitor host immunity among patients with tuberculosis during therapy and vaccine studies.

Original languageEnglish (US)
Pages (from-to)603-615
Number of pages13
JournalJournal of Infectious Diseases
Volume208
Issue number4
DOIs
StatePublished - Aug 15 2013

Bibliographical note

Funding Information:
Financial support. This work was supported by the Department of Biotechnology; the Indian Council of Medical Research, New Delhi, India; and the All India Institute of Medical Sciences. Potential conflicts of interest. All authors: No reported conflicts.

Keywords

  • APCs and apoptosis
  • Programmed death-1
  • T cells
  • Tuberculosis

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