Bi-Allelic Mutations in STXBP2 Reveal a Complementary Role for STXBP1 in Cytotoxic Lymphocyte Killing
| Autor: | Joseph A. Trapani, Natasha J Brown, Jamie A. Lopez, Phillip K. Darcy, Adrian G. Minson, Michael H. Kershaw, Lu Li Jovanoska, Tahereh Noori, Ilia Voskoboinik, Andrew Grigg, Kevin Y. T. Thia, Michael S. Hildebrand, Hedieh Akhlaghi |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
0301 basic medicine Cytotoxicity Immunologic Munc18 Proteins Cell Degranulation Lymphocyte Immunology Case Report familial haemophagocytic lymphohistiocytosis Exocytosis Cell Line 03 medical and health sciences 0302 clinical medicine cytotoxic lymphocytes medicine Immunology and Allergy Syntaxin Cytotoxic T cell Humans Alleles natural killer cells biology Chemistry cytotoxic T cells Degranulation apoptosis Middle Aged 3. Good health Cell biology Killer Cells Natural 030104 developmental biology medicine.anatomical_structure Perforin 030220 oncology & carcinogenesis Munc18-1 Mutation Munc18-2 biology.protein Leukocytes Mononuclear Female lcsh:RC581-607 immunodeficiency T-Lymphocytes Cytotoxic |
| Zdroj: | Frontiers in Immunology Frontiers in Immunology, Vol 9 (2018) |
| ISSN: | 1664-3224 |
| Popis: | The ability of cytotoxic lymphocytes (CL) to eliminate virus-infected or cancerous target cells through the granule exocytosis death pathway is critical to immune homeostasis. Congenital loss of CL function due to bi-allelic mutations in PRF1, UNC13D, STX11, or STXBP2 leads to a potentially fatal immune dysregulation, familial haemophagocytic lymphohistiocytosis (FHL). This occurs due to the failure of CLs to release functional pore-forming protein perforin and, therefore, inability to kill the target cell. Bi-allelic mutations in partner proteins STXBP2 or STX11 impair CL cytotoxicity due to failed docking/fusion of cytotoxic secretory granules with the plasma membrane. One unique feature of STXBP2- and STX11-deficient patient CLs is that their short-term in vitro treatment with a low concentration of IL-2 partially or completely restores natural killer (NK) cell degranulation and cytotoxicity, suggesting the existence of a secondary, yet unknown, pathway for secretory granule exocytosis. In the current report, we studied NK and T-cell function in an individual with late presentation of FHL due to hypomorphic bi-allelic mutations in STXBP2. Intriguingly, in addition to the expected alterations in the STXBP2 and STX11 proteins, we also observed a concomitant significant reduction in the expression of homologous STXBP1 protein and its partner STX1, which had never been implicated in CL function. Further analysis of human NK and T cells demonstrated a functional role for the STXBP1/STX1 axis in NK and CD8+ T-cell cytotoxicity, where it appears to be responsible for as much as 50% of their cytotoxic activity. This discovery suggests a unique and previously unappreciated interplay between STXBP/Munc proteins regulating the same essential granule exocytosis pathway. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|