학술논문
Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect
Document Type
Article
Author
Kögl, Tamara; Chang, Hsin-Fang; Staniek, Julian; Chiang, Samuel C.C.; Thoulass, Gudrun; Lao, Jessica; Weißert, Kristoffer; Dettmer-Monaco, Viviane; Geiger, Kerstin; Manna, Paul T.; Beziat, Vivien; Momenilandi, Mana; Tu, Szu-Min; Keppler, Selina J.; Pattu, Varsha; Wolf, Philipp; Kupferschmid, Laurence; Tholen, Stefan; Covill, Laura E.; Ebert, Karolina; Straub, Tobias; Groß, Miriam; Gather, Ruth; Engel, Helena; Salzer, Ulrich; Schell, Christoph; Maier, Sarah; Lehmberg, Kai; Cornu, Tatjana I.; Pircher, Hanspeter; Shahrooei, Mohammad; Parvaneh, Nima; Elling, Roland; Rizzi, Marta; Bryceson, Yenan T.; Ehl, Stephan; Aichele, Peter; Ammann, Sandra
Source
The Journal of Experimental Medicine; July 2024, Vol. 221 Issue: 7 pe20221122-e20221122, 1p
Subject
Language
ISSN
00221007; 15409538
Abstract
SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11−/− CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell–B cell interactions. Deficiency in STX11 impairs CD4 T cell–dependent B cell differentiation and humoral responses.