Hemophagocytic lymphohistiocytosis in syntaxin-11–deficient mice: T-cell exhaustion limits fatal disease

Abstract

Key Points• Syntaxin-11-deficient mice as the first animal model for human familial hemophagocytic lymphohistiocytosis type 4 (FHL4).• T-cell exhaustion limits HLH progression in syntaxin-11-deficient mice. IntroductionCytolytic activity is a key function of cytotoxic T lymphocytes (CTLs) and NK cells to eliminate infected and malignant cells. Thereby, cytotoxicity is mediated by polarized exocytosis of lytic granules at the immunological synapse. Lytic granules are secretory lysosomes containing effector molecules, such as perforin and granzymes. On interaction with target cells, CTLs undergo polarization, characterized by Ca 2ϩ mobilization, reorientation of the microtubule organization center, and directed movement of lytic granules. The docking-priming-fusion steps of lytic granules are tightly controlled and result in the release of effector molecules at the immunological synapse. Synaptogamin-like proteins, members of the Rab and the Sec1/Munc18 protein families, as well as SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins are involved in this process. SNARE proteins are helical transmembrane molecules expressed on the vesicle and target membranes. On association, they build a trans-SNARE complex, which leads to the fusion of docked lipid bilayers. 1 Syntaxin-11 (Stx11) is an atypical member of the Q-SNARE family and expressed in various cells of the immune system. 2-8 Stx11 associates with Vti1b, 7,9 SNAP23, 10 and syntaxin binding protein 2 (STXBP2/Munc18-2), 11,12 regulating the fusion of lytic granules with the plasma membrane at the immunological synapse. Consistent with this, CTLs and NK cells from patients with mutated STX11 gene or with experimentally reduced Stx11 expression levels displayed defects in degranulation and cytolytic activities. 5,6 In addition, it was described recently that Stx11 plays a role in platelet exocytosis. 13 Patients with mutations in the STX11 gene develop hemophagocytic lymphohistiocytosis (HLH), a lifethreatening disorder of severe hyperinflammation resulting from immune dysregulation. 4,6,14 HLH is associated with defects in components of the cytolytic machinery of T and NK cells [15][16][17][18] and characterized by inflammatory processes in various tissues as a result of infiltrating, hyperactive T cells, NK cells and macrophages, accompanied by massive cytokine production (IFN-␥, TNF-␣, . 19 Because of this loss in immune There is an Inside Blood commentary on this article in this issue.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From homeostasis, patients present with prolonged fever, hepatosplenomegaly, neurologic manifestations, hypercytokinemia, and hemophagocytosis. The diagnostic criteria for HLH according to the Histiocyt...

Crucial role of the hydrophobic pocket region of Munc18 protein in mast cell degranulation

“…S3). At first, this was unexpected because mutations in syntaxin-11 cause severe reductions in secretion from CTLs, NK cells, neutrophils, and platelets in patients with FHL4, as well as recently established syntaxin-11 knockout mice (10,(40)(41)(42). However, our result is consistent with that seen in syntaxin-11 knockout mice, in which mast cell degranulation was not significantly impaired (42).…”

SM protein Munc18-2 facilitates transition of Syntaxin 11-mediated lipid mixing to complete fusion for T-lymphocyte cytotoxicity

“…CTLs from STX11 knockout mice (47,48) and of patients with F-HLH-4 and -5, which have mutations in STX11 and Munc18-2, respectively (7, 17, 49), display reduced cytotoxic activity toward sensitive target cells. In particular, the defective cytotoxic activity associated with F-HLH-associated missense mutations STX11-L58P (50), Munc18-2-E132A (34) and Munc18-2-R65Q (33), which interfere with the STX11/Munc18-2 association, reflect a direct role of this interaction for mediating lytic granule content release.…”

A novel immunoregulatory role for NK-cell cytotoxicity in protection from HLH-like immunopathology in mice

“…Cytotoxic-deficient mice (such as Prf1, Rab27a, Unc13d, Stx11, and Lyst mice) develop a severe HLH-like syndrome after infection with lymphocytic choriomeningitis virus (LCMV). [13][14][15][16][17][18] In the absence of cytotoxic activity of CD8 T cells, an accumulation of the antigen-presenting cells that continuously activate CTLs was reported in Prf1 2/2 mice. 19 The hyperactivated CTLs secrete high levels of interferon (IFN)-g, which appears critical for the development of HLH-like symptoms.…”