title: Comparison of primary human cytotoxic T-cell and natural killer cell responses reveal similar molecular requirements for lytic granule exocytosis but differences in cytokine production.
abstract: Cytotoxic lymphocytes, encompassing cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, kill pathogen-infected, neoplastic, or certain hematopoietic cells through the release of perforin-containing lytic granules. In the present study, we first performed probability-state modeling of differentiation and lytic granule markers on CD8(+) T cells to enable the comparison of bona fide CTLs with NK cells. Analysis identified CD57(bright) expression as a reliable phenotype of granule marker-containing CTLs. We then compared CD3(+)CD8(+)CD57(bright) CTLs with NK cells. Healthy adult peripheral blood CD3(+)CD8(+)CD57(bright) CTLs expressed more granzyme B but less perforin than CD3(-)CD56(dim) NK cells. On stimulation, such CTLs degranulated more readily than other T-cell subsets, but had a propensity to degranulate that was similar to NK cells. Remarkably, the CTLs produced cytokines more rapidly and with greater frequency than NK cells. In patients with biallelic mutations in UNC13D, STX11, or STXBP2 associated with familial hemophagocytic lymphohistiocytosis, CTL and NK cell degranulation were similarly impaired. Therefore, cytotoxic lymphocyte subsets have similar requirements for Munc13-4, syntaxin-11, and Munc18-2 in lytic granule exocytosis. The present results provide a detailed comparison of human CD3(+)CD8(+)CD57(bright) CTLs and NK cells and suggest that analysis of CD57(bright) CTL function may prove useful in the diagnosis of primary immunodeficiencies including familial hemophagocytic lymphohistiocytosis.
authors.affiliation: Centre for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Samuel C C
authors.initials: SC
authors.lastname: Chiang
authors.forename: Jakob
authors.initials: J
authors.lastname: Theorell
authors.forename: Miriam
authors.initials: M
authors.lastname: Entesarian
authors.forename: Marie
authors.initials: M
authors.lastname: Meeths
authors.forename: Monika
authors.initials: M
authors.lastname: Mastafa
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.forename: Per
authors.initials: P
authors.lastname: Frisk
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Gilmour
authors.forename: Marianne
authors.initials: M
authors.lastname: Ifversen
authors.forename: Cecilia
authors.initials: C
authors.lastname: Langenskiöld
authors.forename: Maciej
authors.initials: M
authors.lastname: Machaczka
authors.forename: Ahmed
authors.initials: A
authors.lastname: Naqvi
authors.forename: Jeanette
authors.initials: J
authors.lastname: Payne
authors.forename: Antonio
authors.initials: A
authors.lastname: Perez-Martinez
authors.forename: Magnus
authors.initials: M
authors.lastname: Sabel
authors.forename: Ekrem
authors.initials: E
authors.lastname: Unal
authors.forename: Sule
authors.initials: S
authors.lastname: Unal
authors.forename: Jacek
authors.initials: J
authors.lastname: Winiarski
authors.forename: Magnus
authors.initials: M
authors.lastname: Nordenskjöld
authors.forename: Hans-Gustaf
authors.initials: HG
authors.lastname: Ljunggren
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D018959:CD57 Antigens / Q000378:metabolism*; D016827:CD8 Antigens / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism*; D005089:Exocytosis / Q000276:immunology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism*; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051938:Munc18 Proteins / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D017252:CD3 Complex; D018959:CD57 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D008565:Membrane Proteins; D051938:Munc18 Proteins; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D050765:Qa-SNARE Proteins; C541732:STX11 protein, human; C497940:STXBP2 protein, human; C507969:UNC13D protein, human; D054353:Perforin