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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01983

HIV infection is associated with downregulation of BTLA expression on Mycobacterium tuberculosis-specific CD4 T cells in active tuberculosis disease

Morgan S. Barham1, Deborah A. Abrahams2, Jeremiah Khayumbi3, Joshua Ongalo3, Joan Tonui3,  Angela Campbell4, Marwou de Kock2, Felix H. Odhiambo3, Samuel G. Ouma3,  Neel Gandhi4,  Willem Hanekom2 and  Cheryl L. Day4*
  • 1Emory Vaccine Center, Emory University, United States
  • 2South African Tuberculosis Vaccine Initiative SATVI, South Africa
  • 3Centre for Global Health Research, Kenya Medical Research Institute (KEMRI), Kenya
  • 4Emory University, United States

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 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-g+/TNF-a+ 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.

Keywords: HIV, Mycobacterium tuberculosis, CD4 T cell, BTLA, B and T lymphocyte attenuator, LTBI (Latent TB infections), active tuberculosis disease, CTLA- 4, PD-1

Received: 21 May 2019; Accepted: 06 Aug 2019.

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  

Copyright: © 2019 Barham, Abrahams, Khayumbi, Ongalo, Tonui, Campbell, de Kock, Odhiambo, Ouma, Gandhi, Hanekom and Day. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Cheryl L. Day, Emory University, Atlanta, 30322, Georgia, United States,