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Author Notes:

Cheryl L. Day cday@emory.edu

CD, WB, and WH contributed conception and design of the study.

DA and RB performed experimental work.

CD, WB, and WH contributed to execution and oversight of experimental work.

CD contributed to data interpretation, statistical analyses, and drafted the manuscript.

LS, MdK, GW, and RW contributed reagents, materials, and/or analysis tools.

All authors approved the final manuscript.

We thank the study participants for their time and commitment to the study.

We also thank many additional members of the South African Tuberculosis Vaccine Initiative team who helped with enrollment and evaluation of participants; the clinical staff at the Ubuntu HIV-TB clinic; and the bronchoscopy suite at Tygerberg Academic Hospital, for providing essential support.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Research Funding:

This study was funded by a grant to CD from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (R01AI083156).

RB was supported through the Carnegie Corporation, the University of Cape Town, and the Canada Africa Prevention Trials (CAPT) Network.

RW is supported by Francis Crick Institute, which receives support from Cancer Research UK (FC00110218) and Medical Research Council UK (FC00110218); RW also receives support from Wellcome Trust (104803, 203135) and the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (U01AI115940).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • CD4 T cell
  • CD8 T cell
  • tuberculosis
  • PD-1
  • IFN-gamma
  • proliferation
  • CD8(+) T

PD-1 Expression on Mycobacterium tuberculosis-Specific CD4 T Cells Is Associated With Bacterial Load in Human Tuberculosis


Journal Title:

Frontiers in Immunology


Volume 9


, Pages 1995-1995

Type of Work:

Article | Final Publisher PDF


Persistent antigen stimulation in chronic infections has been associated with antigen-specific T cell dysfunction and upregulation of inhibitory receptors, including programmed cell death protein 1 (PD-1). Pulmonary tuberculosis (TB) disease is characterized by high levels of Mycobacterium tuberculosis (Mtb), yet the relationship between bacterial load, PD-1 expression, and Mtb-specific T cell function in human TB has not been well-defined. Using peripheral blood samples from adults with LTBI and with pulmonary TB disease, we tested the hypothesis that PD-1 expression is associated with bacterial load and functional capacity of Mtb-specific T cell responses. We found that PD-1 was expressed at significantly higher levels on Th1 cytokine-producing Mtb-specific CD4 T cells from patients with smear-positive TB, compared with smear-negative TB and LTBI, which decreased after completion of anti-TB treatment. By contrast, expression of PD-1 on Mtb-specific CD8 T cells was significantly lower than on Mtb-specific CD4 T cells and did not differ by Mtb infection and disease status. In vitro stimulation of PBMC with Mtb antigens demonstrated that PD-1 is induced on proliferating Mtb-specific CD4 T cells and that Th1 cytokine production capacity is preferentially maintained within PD-1+ proliferating CD4 T cells, compared with proliferating Mtb-specific CD4 T cells that lack PD-1 expression. Together, these data indicate that expression of PD-1 on Mtb-specific CD4 T cells is indicative of mycobacterial antigen exposure and identifies a population of effector cells with Th1 cytokine production capacity. These studies provide novel insights into the role of the PD-1 pathway in regulating CD4 and CD8 T cell responses in Mtb infection and provide rationale for future studies to evaluate PD-1 expression on antigen-specific CD4 T cells as a potential biomarker for bacterial load and treatment response in human TB.

Copyright information:

© 2018 Day, Abrahams, Bunjun, Stone, de Kock, Walzl, Wilkinson, Burgers and Hanekom.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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