Patients and Mice With Deficiency in the Snare Protein Syntaxin-11 Have a Secondary B Cell Defect Publisher Pubmed

Summary: Immune weakness? Study links STX11 defects to FHL-4, low antibodies—impairs CD4 T cells. Suggests therapy targets. #Immunodeficiency #HumoralImmunity

Kogl T^{1, 2} ; Chang HF³ ; Staniek J^{4, 5} ; Chiang SCC^{6, 7} ; Thoulass G^{2, 4, 8} ; Lao J^{2, 4, 8} ; Weiert K^{2, 4} ; Dettmermonaco V^{4, 9} ; Geiger K^{4, 8, 9} ; Manna PT¹⁰ ; Beziat V^{11, 12, 13} ; Momenilandi M^{11, 12} ; Tu SM³ ; Keppler SJ¹⁴ Show All Authors
Source: The Journal of experimental medicine Published: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. © 2024 Kogl et al.