title: Circulating mycobacterial-reactive CD4+ T cells with an immunosuppressive phenotype are higher in active tuberculosis than latent tuberculosis infection.
abstract: BACKGROUND
  Previous studies suggest that control of Mycobacterium tuberculosis infection is compromised by the activity of regulatory T cells, including those that express CD39, an ectonucleotidase with immunosuppressive properties. Here, we examine the role of CD39 on CD4+ T cells reacting to M. tuberculosis antigens.
  
  
  METHODS
  Cryopreserved PBMC from patients with active TB (n = 31) or individuals with LTBI (n = 30) were cultured with PPD, ESAT-6 or CFP-10 and antigen-reactive CD4+ T cells assessed by: A) intracellular expression of interferon-gamma (IFN-γ), tumour necrosis factor alpha (TNF-α) and interleukin (IL)-2, B) co-expression of CD25 and CD134 with or without CD39, and C) production of IFN-γ, TNF-α and IL-10 in culture supernatants.
  
  
  RESULTS
  Active TB patients were not differentiated from individuals with LTBI by intracellular expression of IFN-γ, TNF-α or IL-2 (alone or together), nor by co-expression of CD25 and CD134. However, active TB patients exhibited higher proportions of CD25+, CD134+, CD4+ T cells expressing CD39 in response to all antigens (p ≤ 0.022). Furthermore, in response to PPD, CD39 expression on CD25+, CD134+, CD4+ T cells correlated with IL-10 production (r = 0.41, p = 0.005) and inhibition of CD39 decreased IL-10 production.
  
  
  CONCLUSIONS
  Antigen-reactive CD4+ T cells expressing CD39 are more abundant in active TB than LTBI and are associated with production of the immunosuppressive cytokine IL-10. Modulating the effects of CD39 might enhance cellular immune responses against M. tuberculosis.
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Kim
authors.affiliation: Tuberculosis Control Program, Health Department of Western Australia, Perth, Australia.
authors.forename: R
authors.initials: R
authors.lastname: Perera
authors.affiliation: Centre for Asthma, Allergy and Respiratory Research, Lung Institute of Western Australia, Perth, Australia.
authors.forename: D B A
authors.initials: DB
authors.lastname: Tan
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Fernandez
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France; Vaccine Research Institute (VRI) and Université Paris-Est Créteil, France.
authors.forename: N
authors.initials: N
authors.lastname: Seddiki
authors.affiliation: Tuberculosis Control Program, Health Department of Western Australia, Perth, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Waring
authors.affiliation: School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia; Department of Clinical Immunology and PathWest Laboratory Medicine, Royal Perth Hospital, Perth, Australia. Electronic address: martyn.french@uwa.edu.au.
authors.forename: M A
authors.initials: MA
authors.lastname: French
mesh_terms: D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001081:Apyrase / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D055985:Latent Tuberculosis / Q000097:blood / Q000175:diagnosis / Q000276:immunology* / Q000382:microbiology; D008213:Lymphocyte Activation; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000472:pathogenicity; D010641:Phenotype; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014376:Tuberculosis / Q000097:blood / Q000276:immunology* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D015703:Antigens, CD; C573415:IFNG protein, human; C508609:IL10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D001081:Apyrase; C067869:CD39 antigen
keywords: Antigen-reactive T cells; CD39; IL-10; Tuberculosis