Defective cytotoxic lymphocyte degranulation in syntaxin-11–deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients

Abstract

Familial hemophagocytic lymphohistiocytosis (FHL) is

Syntaxin 11 is required for NK and CD8+ T‐cell cytotoxicity and neutrophil degranulation

“…This is in concert with previous findings in lymphocytes from healthy donors and FHL type 4 patient samples showing that a deficiency in STX11 leads to an impaired degranulation and cytotoxic activity [4,5]. Thus, Stx11 −/− mice that were found to carry no overt defect in immune system development and immune cell populations in lymphatic tissues could be an ideal in vivo model for further dissecting the Hemophagocytic Lymphohistiocytosis (HLH) pathogenesis, in particular FHL-4 which is caused by a mutated STX11 gene in humans [13].…”

“…Defective NK cell degranulation and cytotoxicity have been identified in patients with FHL-4, which correlates with a deficiency in STX11 expression [5,13]. Therefore we investigated whether a constitutive deficiency of STX11 in NK cells and CTL results in dysregulated degranulation and granule exocytosis in both cell types and whether this altered effector function correlates with a specific NK or CD8 + T-cell phenotype.…”

“…STX11 is expressed in a wide variety of cells including human monocytes/macrophages, neutrophils, B cells, NK cells and CD8 + T cells [2][3][4][5][6][7][8][9]. STX11 is enriched in immune tissues such as thymus, spleen C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur.…”

“…de and is involved in intracellular membrane trafficking events by interacting with other family members or by associating with membranes by palmitoylation of cysteine residues [1][2][3]. STX11 is expressed in a wide variety of cells including human monocytes/macrophages, neutrophils, B cells, NK cells and CD8 + T cells [2][3][4][5][6][7][8][9]. STX11 is enriched in immune tissues such as thymus, spleen Values represent the mean ± SEM percentage of cell subsets in the spleen (n = 8) and lymph nodes (WT n = 7; Stx11 −/− n = 6) and are the summary of three experiments performed.…”

“…STX11 localizes mainly in the vesicular tubular clusters, an organelle complex between the endoplasmic reticulum and the Golgi, and displays, in addition, a spotted staining pattern throughout the cell periphery [2,9]. While STX11 has been recognized to act as a negative regulator of both phagocytosis and intracellular trafficking between endosomes, lysosomes and the outer membrane in macrophages [6,9], in human NK cells and CTLs, STX11 has been suggested to regulate granule exocytosis and cytotoxicity [4,5].Several disease-causing mutations have been identified in genes encoding for various components of the cytolytic machinery, including the pore-forming protein perforin, the proteins belonging to the exocytic machinery (e.g. MUNC13-4 and Rab27a) and STX11 [10][11][12][13].…”