title: Tuberculosis Therapy Modifies the Cytokine Profile, Maturation State, and Expression of Inhibitory Molecules on Mycobacterium tuberculosis-Specific CD4+ T-Cells.
abstract: BACKGROUND
  Little is known about the expression of inhibitory molecules cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed-death-1 (PD-1) on Mycobacterium tuberculosis (Mtb)-specific CD4 T-cells and how their expression is impacted by TB treatment.
  
  
  METHODS
  Cryopreserved PBMCs from HIV-TB co-infected and TB mono-infected patients with untreated and treated tuberculosis (TB) disease were stimulated for six hours with PPD and stained. Using polychromatic flow cytometry, we characterized the differentiation state, cytokine profile, and inhibitory molecule expression on PPD-specific CD4 T-cells.
  
  
  RESULTS
  In our HIV-TB co-infected cohort, TB treatment increased the proportion of PPD-specific CD4 T-cells co-producing IFN-γ+IL-2+TNF-α+ and IFN-γ+IL-2+ (p = 0.0004 and p = 0.0002, respectively) while decreasing the proportion of PPD-specific CD4 T-cells co-producing IFN-γ+MIP1-β+TNF-α+ and IFN-γ+MIP1-β+. The proportion of PPD-specific CD4 T-cells expressing an effector memory phenotype decreased (63.6% vs 51.6%, p = 0.0015) while the proportion expressing a central memory phenotype increased (7.8% vs. 21.7%, p = 0.001) following TB treatment. TB treatment reduced the proportion of PPD-specific CD4 T-cells expressing CTLA-4 (72.4% vs. 44.3%, p = 0.0005) and PD-1 (34.5% vs. 29.2%, p = 0.03). Similar trends were noted in our TB mono-infected cohort.
  
  
  CONCLUSIONS
  TB treatment alters the functional profile of Mtb-specific CD4 T-cells reflecting shifts towards a less differentiated maturational profile and decreases PD-1 and CTLA-4 expression. These could serve as markers of reduced mycobacterial burden. Further study is warranted.
authors.affiliation: Institute of Human Virology and Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, MD, United States of America.|Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Kapil K
authors.initials: KK
authors.lastname: Saharia
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Petrovas
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.|Laboratorio de InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.|Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Ferrando-Martinez
authors.affiliation: Laboratory of Immunovirology, Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Leal
authors.affiliation: Department of Infectious Diseases, Microbiology and Preventive Medicine, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Luque
authors.affiliation: Clinical HIV Research Unit, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Prudence
authors.initials: P
authors.lastname: Ive
authors.affiliation: Division of HIV, Infectious Diseases and Global Medicine, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Anne
authors.initials: A
authors.lastname: Luetkemeyer
authors.affiliation: Division of HIV, Infectious Diseases and Global Medicine, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Diane
authors.initials: D
authors.lastname: Havlir
authors.affiliation: Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States of America.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D013045:Species Specificity; D014376:Tuberculosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism
chemical_list: D000995:Antitubercular Agents; D060908:CTLA-4 Antigen; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor