title: HIV Skews the Lineage-Defining Transcriptional Profile of Mycobacterium tuberculosis-Specific CD4+ T Cells.
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.
authors.affiliation: 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.
authors.forename: Catherine
authors.initials: C
authors.lastname: Riou
authors.affiliation: 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;
authors.forename: Natalie
authors.initials: N
authors.lastname: Strickland
authors.affiliation: 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;
authors.forename: Andreia P
authors.identifier: http://orcid.org/0000-0002-9003-222X
authors.initials: AP
authors.lastname: Soares
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02139;
authors.forename: Björn
authors.identifier: http://orcid.org/0000-0001-9833-3169
authors.initials: B
authors.lastname: Corleis
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139; Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA 02139;
authors.forename: Douglas S
authors.identifier: http://orcid.org/0000-0001-8521-8735
authors.initials: DS
authors.lastname: Kwon
authors.affiliation: Department of Microbiology, Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.affiliation: 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.
authors.forename: Robert J
authors.identifier: http://orcid.org/0000-0002-2753-1800
authors.initials: RJ
authors.lastname: Wilkinson
authors.affiliation: 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;
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Burgers
mesh_terms: D000328:Adult; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D016022:Case-Control Studies; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D060085:Coinfection; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome; D014373:Tuberculin / Q000276:immunology; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D019562:Viral Load; D055815:Young Adult
chemical_list: D016207:Cytokines; D014157:Transcription Factors; D014373:Tuberculin