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

• Published in: Frontiers in immunology Vol. 10; p. 1983
• Main Authors: Barham, Morgan S, Abrahams, Deborah A, Khayumbi, Jeremiah, Ongalo, Joshua, Tonui, Joan, Campbell, Angela, de Kock, Marwou, Ouma, Samuel Gurrion, Odhiambo, Felix Hayara, Hanekom, Willem A, Gandhi, Neel R, Day, Cheryl L
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 2019
• Subjects: active TB disease; Adult; BTLA; CD4 T cell; CD4-Positive T-Lymphocytes - immunology; Down-Regulation; Female; HIV; HIV Infections - immunology; Humans; Immunology; LTBI; Male; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; Receptors, Immunologic - immunology; Tuberculosis - immunology; Young Adult; HIV; Mycobacterium tuberculosis; BTLA; CD4 T cell; CTLA-4; active TB disease; LTBI; PD-1
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2019.01983

Nearly a quarter of the global population is infected with (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.