title: Activation of NK cell granulysin by mycobacteria and IL-15 is differentially affected by HIV.
abstract: NK cells play an important role in innate immunity to mycobacteria and are a significant source of the bactericidal effector molecule granulysin. Defects in NK cells have been described in HIV-infected patients, though mechanistic studies have focused on effector molecules relevant to anti-viral, and not anti-bacterial, function. Here we used primary NK cells from healthy human donors and an in vitro system to identify the phenotype of granulysin expressing NK cells, characterize activation stimuli that regulate granulysin, and to study the immediate effects of HIV on innate activation of NK cell granulysin expression. We observe that granulysin expression is co-associated with cytotoxicity receptors (NKp46, NKG2D) known to have important function in the cytotoxic response to M.tb-infected macrophages. Granulysin expression is significantly increased following exposure to IL-15 or Mycobacterium bovis BCG, but in contrast to our previous findings with CD8(+)T cells, expression is weakly activated by IL-21. Infection of PBMC with HIV-1 suppresses NK cell induction of granulysin by IL-15, but does not impair activation by BCG. These effects of HIV-1 are associated with reduced STAT5 phosphorylation in the IL-15 activated signaling cascade. These observations suggest that HIV may impair the anti-bacterial function of NK cells and have implications for clinical use of IL-15 to augment innate cell mediated immunity in HIV+ patients.
authors.affiliation: National Institutes of Health, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Hogg
authors.forename: Matthew
authors.initials: M
authors.lastname: Huante
authors.forename: Asiko
authors.initials: A
authors.lastname: Ongaya
authors.forename: Jessica
authors.initials: J
authors.lastname: Williams
authors.forename: Monique
authors.initials: M
authors.lastname: Ferguson
authors.forename: Miles
authors.initials: M
authors.lastname: Cloyd
authors.forename: Evans
authors.initials: E
authors.lastname: Amukoye
authors.forename: Janice
authors.initials: J
authors.lastname: Endsley
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000097:blood*; D002478:Cells, Cultured; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1; D006801:Humans; D016130:Immunophenotyping; D019409:Interleukin-15 / Q000276:immunology; D007694:Killer Cells, Natural / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D009163:Mycobacterium bovis / Q000276:immunology*; D010766:Phosphorylation / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C075005:GNLY protein, human; D019409:Interleukin-15; D050799:STAT5 Transcription Factor