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Author Notes:

Cheryl L. Day: cday@emory.edu

Edited by: Remy Bosselut, National Cancer Institute (NCI), United States

Reviewed by: Anna-Lena Spetz, Stockholm University, Sweden; Juraj Ivanyi, King's College London, United Kingdom

CD and MB contributed conception and design of the study and data interpretation, statistical analyses, and drafted the manuscript.

MB, DA, JK, JO, and JT performed experimental work.

CD, MB, SO, FO, MdK, AC, NG, and WH contributed to execution and oversight of experimental work, participant recruitment and enrollment, and study database management.

All authors approved the final manuscript.

We thank many additional members of the South African Tuberculosis Vaccine Initiative (SATVI) team and the Kenya Medical Research Institute (KEMRI)/Centers for Disease Control and Prevention (CDC) team who helped with enrollment and evaluation of participants, and the participants themselves.

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 supported by grants to CD from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (5R01AI083156, 5R01AI111948, U19AI111211). MB was supported by a Research Supplement to Promote Diversity in Health-Related Research from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (3R01AI111948-03S1).

NG was supported by grants from the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (K24AI114444, U19AI111211).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • HIV
  • Mycobacterium tuberculosis
  • LTBI
  • active TB disease
  • CD4T cell
  • BTLA
  • CTLA-4
  • PD-1

HIV Infection Is Associated With Downregulation of BTLA Expression on Mycobacterium tuberculosis-Specific CD4T Cells in Active Tuberculosis Disease

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Journal Title:

Frontiers in Immunology


Volume 10, Number AUG


, Pages 1983-1983

Type of Work:

Article | Final Publisher PDF


Nearly a quarter of the global population is infected with Mycobacterium tuberculosis (Mtb), with 10 million people developing active tuberculosis (TB) annually. Co-infection with human immunodeficiency virus (HIV) has long been recognized as a significant risk factor for progression to TB disease, yet the mechanisms whereby HIV impairs T cell-mediated control of Mtb infection remain poorly defined. We hypothesized that HIV infection may promote upregulation of inhibitory receptors on Mtb-specific CD4 T cells, a mechanism that has been associated with antigen-specific T cell dysfunction in chronic infections. Using cohorts of HIV-infected and HIV-uninfected individuals with latent Mtb infection (LTBI) and with active TB disease, we stimulated peripheral blood mononuclear cells (PBMC) for 6 hours with Mtb peptide pools and evaluated co-expression profiles of the inhibitory receptors BTLA, CTLA-4, and PD-1 on IFN-γ+/TNF-α+ Mtb-specific CD4 T cells. Mtb-specific CD4 T cells in all participant groups expressed predominately either one or no inhibitory receptors, unlike cytomegalovirus-and HIV-specific CD4 T cells circulating in the same individuals, which were predominately CTLA-4+ PD-1+. There were no significant differences in inhibitory receptor expression profiles of Mtb-specific CD4 T cells between HIV-uninfected and HIV-infected individuals with LTBI. Surprisingly, BTLA expression, both alone and in combination with CTLA-4 and PD-1, was markedly downregulated on Mtb-specific CD4 T cells in HIV-infected individuals with active TB. Together, these data provide novel evidence that the majority of Mtb-specific CD4 T cells do not co-express multiple inhibitory receptors, regardless of HIV infection status; moreover, they highlight a previously unrecognized role of BTLA expression on Mtb-specific CD4 T cells that could be further explored as a potential biomarker of Mtb infection status, particularly in people living with HIV, the population at greatest risk for development of active TB disease.

Copyright information:

© 2019 Barham, Abrahams, Khayumbi, Ongalo, Tonui, Campbell, de Kock, Ouma, Odhiambo, Hanekom, Gandhi and Day.

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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