title: PD-1, PD-L1 and PD-L2 Gene Expression on T-Cells and Natural Killer Cells Declines in Conjunction with a Reduction in PD-1 Protein during the Intensive Phase of Tuberculosis Treatment.
abstract: BACKGROUND
  The PD-1 axis is a cell intrinsic immunoregulatory pathway that mediates T cell exhaustion in chronic infection particularly in some viral infections. We hypothesized that PD-1, PD-L1 and PD-L2 would be highly expressed in untreated tuberculosis patients compared to controls due to their chronic infection and would decrease with successful TB treatment.
  
  
  METHODS
  Untreated tuberculosis patients (n = 26) were recruited at diagnosis and followed up during treatment. Household contacts (n = 24) were recruited to establish baseline differences. Blood gene expression ex vivo was investigated using qRT-PCR. Flow cytometry was performed to establish protein expression patterns.
  
  
  RESULTS
  PD-L1 gene expression was found to be elevated in active TB disease; however, this was not observed for PD-1 or PD-L2. The intensive phase of TB treatment was associated with a significant decline in PD-1, PD-L1 and PD-L2 gene expression. PD-1 protein expression on the surface of NK cells, CD8+ and CD4+ T cells was similar in patients with active TB disease compared to controls but declined with successful TB treatment, with the greatest decline occurring on the NK cells followed by CD8+ T cells and then CD4+ T cells. Granzyme B/PD-1 co-expression declined with successful intensive phase treatment.
  
  
  CONCLUSIONS
  Modulation of PD-1/PD-L1 pathway through TB treatment indicates changes in the peripheral T cell response caused by live Mycobacterium tuberculosis (Mtb) followed by the response to dead bacilli, antigen-release and immuno-pathology resolution. The PD-1 axis could be a host drug target for immunomodulatory treatments in the future.
authors.affiliation: Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, United Kingdom.
authors.forename: Syeda S
authors.initials: SS
authors.lastname: Hassan
authors.affiliation: Gulab Devi Chest Hospital, Lahore, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Akram
authors.affiliation: Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, United Kingdom.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: King
authors.affiliation: Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, United Kingdom.
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Dockrell
authors.affiliation: Department of Immunology and Infection, London School of Hygiene & Tropical Medicine, London, WC1E 7HT, United Kingdom.
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Cliff
mesh_terms: D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics* / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D014376:Tuberculosis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D060890:B7-H1 Antigen; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor