Abstract
Originalsprog | Engelsk |
---|---|
Tidsskrift | Blood |
Vol/bind | 114 |
Udgave nummer | 19 |
Sider (fra-til) | 4117-27 |
Antal sider | 10 |
ISSN | 0006-4971 |
DOI | |
Status | Udgivet - 2009 |
Bibliografisk note
Keywords: Case-Control Studies; Cell Degranulation; Child; Cytoplasmic Granules; Cytotoxicity, Immunologic; Humans; Ionomycin; Killer Cells, Natural; Lymphocyte Activation; Lymphocyte Function-Associated Antigen-1; Lymphohistiocytosis, Hemophagocytic; Membrane Proteins; Mutation; Perforin; Receptors, IgG; Receptors, Immunologic; Signal Transduction; Tetradecanoylphorbol Acetate; rab GTP-Binding ProteinsAdgang til dokumentet
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Different NK cell-activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity. / Wood, Stephanie M; Meeths, Marie; Chiang, Samuel C C; Bechensteen, Anne Grete; Boelens, Jaap J; Heilmann, Carsten; Horiuchi, Hisanori; Rosthøj, Steen; Rutynowska, Olga; Winiarski, Jacek; Stow, Jennifer L; Nordenskjöld, Magnus; Henter, Jan-Inge; Ljunggren, Hans-Gustaf; Bryceson, Yenan T.
I: Blood, Bind 114, Nr. 19, 2009, s. 4117-27.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
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TY - JOUR
T1 - Different NK cell-activating receptors preferentially recruit Rab27a or Munc13-4 to perforin-containing granules for cytotoxicity
AU - Wood, Stephanie M
AU - Meeths, Marie
AU - Chiang, Samuel C C
AU - Bechensteen, Anne Grete
AU - Boelens, Jaap J
AU - Heilmann, Carsten
AU - Horiuchi, Hisanori
AU - Rosthøj, Steen
AU - Rutynowska, Olga
AU - Winiarski, Jacek
AU - Stow, Jennifer L
AU - Nordenskjöld, Magnus
AU - Henter, Jan-Inge
AU - Ljunggren, Hans-Gustaf
AU - Bryceson, Yenan T
N1 - Keywords: Case-Control Studies; Cell Degranulation; Child; Cytoplasmic Granules; Cytotoxicity, Immunologic; Humans; Ionomycin; Killer Cells, Natural; Lymphocyte Activation; Lymphocyte Function-Associated Antigen-1; Lymphohistiocytosis, Hemophagocytic; Membrane Proteins; Mutation; Perforin; Receptors, IgG; Receptors, Immunologic; Signal Transduction; Tetradecanoylphorbol Acetate; rab GTP-Binding Proteins
PY - 2009
Y1 - 2009
N2 - The autosomal recessive immunodeficiencies Griscelli syndrome type 2 (GS2) and familial hemophagocytic lymphohistiocytosis type 3 (FHL3) are associated with loss-of-function mutations in RAB27A (encoding Rab27a) and UNC13D (encoding Munc13-4). Munc13-4 deficiency abrogates NK-cell release of perforin-containing lytic granules induced by signals for natural and antibody-dependent cellular cytotoxicity. We demonstrate here that these signals fail to induce degranulation in resting NK cells from Rab27a-deficient patients. In resting NK cells from healthy subjects, endogenous Rab27a and Munc13-4 do not colocalize extensively with perforin. However, phorbol 12-myristate 13-acetate and ionomycin stimulation or conjugation to susceptible target cells induced myosin-dependent colocalization of Rab27a and Munc13-4 with perforin. Unexpectedly, individual engagement of receptors leukocyte functional antigen-1, NKG2D, or 2B4 induced colocalization of Rab27a, but not Munc13-4, with perforin. Conversely, engagement of antibody-dependent cellular cytotoxicity receptor CD16 induced colocalization of Munc13-4, but not Rab27a, with perforin. Furthermore, colocalization of Munc13-4 with perforin was Rab27a-dependent. In conclusion, Rab27a or Munc13-4 recruitment to lytic granules is preferentially regulated by different receptor signals, demonstrating that individual target cell ligands regulate discrete molecular events for lytic granule maturation. The data suggest Rab27a facilitates degranulation at an early step yet highlight a reciprocal relationship between Munc13-4 and Rab27a for degranulation.
AB - The autosomal recessive immunodeficiencies Griscelli syndrome type 2 (GS2) and familial hemophagocytic lymphohistiocytosis type 3 (FHL3) are associated with loss-of-function mutations in RAB27A (encoding Rab27a) and UNC13D (encoding Munc13-4). Munc13-4 deficiency abrogates NK-cell release of perforin-containing lytic granules induced by signals for natural and antibody-dependent cellular cytotoxicity. We demonstrate here that these signals fail to induce degranulation in resting NK cells from Rab27a-deficient patients. In resting NK cells from healthy subjects, endogenous Rab27a and Munc13-4 do not colocalize extensively with perforin. However, phorbol 12-myristate 13-acetate and ionomycin stimulation or conjugation to susceptible target cells induced myosin-dependent colocalization of Rab27a and Munc13-4 with perforin. Unexpectedly, individual engagement of receptors leukocyte functional antigen-1, NKG2D, or 2B4 induced colocalization of Rab27a, but not Munc13-4, with perforin. Conversely, engagement of antibody-dependent cellular cytotoxicity receptor CD16 induced colocalization of Munc13-4, but not Rab27a, with perforin. Furthermore, colocalization of Munc13-4 with perforin was Rab27a-dependent. In conclusion, Rab27a or Munc13-4 recruitment to lytic granules is preferentially regulated by different receptor signals, demonstrating that individual target cell ligands regulate discrete molecular events for lytic granule maturation. The data suggest Rab27a facilitates degranulation at an early step yet highlight a reciprocal relationship between Munc13-4 and Rab27a for degranulation.
U2 - 10.1182/blood-2009-06-225359
DO - 10.1182/blood-2009-06-225359
M3 - Journal article
C2 - 19704116
VL - 114
SP - 4117
EP - 4127
JO - Blood
JF - Blood
SN - 0006-4971
IS - 19
ER -