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J Immunol. 2016 Apr 1;196(7):3006-18. doi: 10.4049/jimmunol.1502094. Epub 2016 Feb 29.

HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis-Specific CD4+ T Cells.

Author information

1
Division of Medical Virology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, 7925, Cape Town, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, 7925, Cape Town, South Africa; c.riou@uct.ac.za.
2
Division of Medical Virology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, 7925, Cape Town, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, 7925, Cape Town, South Africa;
3
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02139;
4
Department of Microbiology, Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
5
Institute of Infectious Disease and Molecular Medicine, University of Cape Town, 7925, Cape Town, South Africa; Department of Medicine, Imperial College London, London W21 PG, United Kingdom; Francis Crick Institute Mill Hill Laboratory, London NW7 1AA, United Kingdom; and Clinical Infectious Diseases Research Initiative, University of Cape Town, 7925, Cape Town, South Africa.

Abstract

HIV-infected persons are at greater risk of developing tuberculosis (TB) even before profound CD4 loss occurs, suggesting that HIV alters CD4(+) T cell functions capable of containing bacterial replication. An effective immune response to Mycobacterium tuberculosis most likely relies on the development of a balanced CD4 response, in which distinct CD4(+) Th subsets act in synergy to control the infection. To define the diversity of M. tuberculosis-specific CD4(+) Th subsets and determine whether HIV infection impacts such responses, the expression of lineage-defining transcription factors T-bet, Gata3, RORγt, and Foxp3 was measured in M. tuberculosis-specific CD4(+) T cells in HIV-uninfected (n = 20) and HIV-infected individuals (n = 20) with latent TB infection. Our results show that, upon 5-d restimulation in vitro, M. tuberculosis-specific CD4(+) T cells from healthy individuals have the ability to exhibit a broad spectrum of Th subsets, defined by specific patterns of transcription factor coexpression. These transcription factor profiles were skewed in HIV-infected individuals where the proportion of T-bet(high)Foxp3(+) M. tuberculosis-specific CD4(+) T cells was significantly decreased (p = 0.002) compared with HIV-uninfected individuals, a change that correlated inversely with HIV viral load (p = 0.0007) and plasma TNF-α (p = 0.027). Our data demonstrate an important balance in Th subset diversity defined by lineage-defining transcription factor coexpression profiles that is disrupted by HIV infection and suggest a role for HIV in impairing TB immunity by altering the equilibrium of M. tuberculosis-specific CD4(+) Th subsets.

PMID:
26927799
PMCID:
PMC4799776
DOI:
10.4049/jimmunol.1502094
[Indexed for MEDLINE]
Free PMC Article

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