AUTHOR=Lopez Jamie A. , Noori Tahereh , Minson Adrian , Li Jovanoska Lu , Thia Kevin , Hildebrand Michael S. , Akhlaghi Hedieh , Darcy Phillip K. , Kershaw Michael H. , Brown Natasha J. , Grigg Andrew , Trapani Joseph A. , Voskoboinik Ilia 

TITLE=Bi-Allelic Mutations in STXBP2 Reveal a Complementary Role for STXBP1 in Cytotoxic Lymphocyte Killing

JOURNAL=Frontiers in Immunology

VOLUME=Volume 9 - 2018

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00529

DOI=10.3389/fimmu.2018.00529

ISSN=1664-3224

ABSTRACT=The ability of cytotoxic lymphocytes (CL) to eliminate virus-infected or cancerous target cells through the granule exocytosis death pathway is critical to immune homoeostasis. 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 to the synaptic cleft between the lymphocyte and a target cell. One unique feature of STXBP2- and STX11- deficient patient cytotoxic lymphocytes is that their short-term in vitro treatment with a low concentration of IL-2 partially or completely restores natural killer cell degranulation and cytotoxicity, suggesting the existence of a secondary, yet unknown, pathway for secretory granule exocytosis. In the current report, we studied natural killer 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, which had never been implicated in CL function. Further analysis of human NK and T cells demonstrated a functional role for STXBP1 in natural killer and CD8+ T-cell cytotoxicity, where it appears to be responsible for as much as 50% of their cytotoxic activity. This discovery provides an explanation for a paradoxical recovery of natural killer cell function in patients with STXBP2 (and, potentially, STX11) mutations, and suggests a unique and previously unappreciated interplay between STXBP/Munc proteins regulating the same essential granule exocytosis pathway.