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Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect

Authors :
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
Publication Year :
2024

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.

Details

Language :
English
ISSN :
00221007 and 15409538
Volume :
221
Issue :
7
Database :
Supplemental Index
Journal :
The Journal of Experimental Medicine
Publication Type :
Periodical
Accession number :
ejs66315190
Full Text :
https://doi.org/10.1084/jem.20221122