HIV Infection Is Associated With Downregulation of BTLA Expression on Mycobacterium tuberculosis-Specific CD4 T Cells in Active Tuberculosis Disease.

Morgan S Barham,Deborah A Abrahams,Cheryl L Day,Felix Hayara Odhiambo,Jeremiah Khayumbi,Willem A Hanekom,Neel R Gandhi,Joshua Ongalo,Samuel Gurrion Ouma,Joan Tonui,Angela Campbell,Marwou De Kock

doi:10.3389/fimmu.2019.01983

Abstract

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.

Highlights

Mycobacterium tuberculosis (Mtb) is the infectious agent that causes tuberculosis (TB) disease [1]
peripheral blood mononuclear cells (PBMC) were stimulated for 6 h with the immunodominant Mtb Ags CFP-10 and ESAT-6 and viral Ags (HCMV pp65 and human immunodeficiency virus (HIV) Gag peptide pools); Agspecific CD4 T cells were identified by production of IFN-γ and TNF-α (Figure 1A)
A state of T cell dysfunction, including dampened effector functions, upregulated inhibitory receptor expression, and decreased proliferation has been described during chronic infections [33], yet the relationship between HIV infection and the phenotype and function of Mtb-specific CD4 T cell responses has not been fully elucidated

Summary

Introduction

Mycobacterium tuberculosis (Mtb) is the infectious agent that causes tuberculosis (TB) disease [1]. In 2017, 10 million new cases of TB disease were reported, resulting in 1.6 million deaths [1]. An estimated 1.7 billion people, representing nearly a quarter of the world’s population, are latently infected with Mtb and at risk for developing active TB disease [2]. The precise immune correlates of protection against TB have not been defined, co-infection with human immunodeficiency virus (HIV) is the single greatest risk factor for reactivation from latent Mtb infection (LTBI) to active TB disease [1, 3]. Worldwide, ∼9% of new reported TB cases occur in people living with HIV, of which 72% live in Africa [1]

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Conclusion