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oai:repisalud.isciii.es:20.500.12105/199342025-03-17T09:48:52Zcom_20.500.12105_2052com_20.500.12105_2051com_20.500.12105_19604com_20.500.12105_15322col_20.500.12105_19609col_20.500.12105_19605col_20.500.12105_16980

00925njm 22002777a 4500 dc Bodega-Mayor, Irene author Delgado-Wicke, Pablo author Arrabal, Alejandro author Alegría-Carrasco, Estíbaliz author Nicolao-Gómez, Ana author Jaén-Castaño, Marta author Espadas, Cristina author Dopazo, Ana author Martín-Gayo, Enrique author Gaspar, Maria Luisa author Andres, Belen de author Fernández-Ruiz, Elena author 2024-04-29 Tyrosine kinase 2 (TYK2) is involved in type I interferon (IFN-I) signaling through IFN receptor 1 (IFNAR1). This signaling pathway is crucial in the early antiviral response and remains incompletely understood on B cells. Therefore, to understand the role of TYK2 in B cells, we studied these cells under homeostatic conditions and following in vitro activation using Tyk2-deficient (Tyk2-/-) mice. Splenic B cell subpopulations were altered in Tyk2-/- compared to wild type (WT) mice. Marginal zone (MZ) cells were decreased and aged B cells (ABC) were increased, whereas follicular (FO) cells remained unchanged. Likewise, there was an imbalance in transitional B cells in juvenile Tyk2-/- mice. RNA sequencing analysis of adult MZ and FO cells isolated from Tyk2-/- and WT mice in homeostasis revealed altered expression of IFN-I and Toll-like receptor 7 (TLR7) signaling pathway genes. Flow cytometry assays corroborated a lower expression of TLR7 in MZ B cells from Tyk2-/- mice. Splenic B cell cultures showed reduced proliferation and differentiation responses after activation with TLR7 ligands in Tyk2-/- compared to WT mice, with a similar response to lipopolysaccharide (LPS) or anti-CD40 + IL-4. IgM, IgG, IL-10 and IL-6 secretion was also decreased in Tyk2-/- B cell cultures. This reduced response of the TLR7 pathway in Tyk2-/- mice was partially restored by IFNα addition. In conclusion, there is a crosstalk between TYK2 and TLR7 mediated by an IFN-I feedback loop, which contributes to the establishment of MZ B cells and to B cell proliferation and differentiation. Bodega-Mayor I, Delgado-Wicke P, Arrabal A, Alegría-Carrasco E, Nicolao-Gómez A, Jaén-Castaño M, Espadas C, Dopazo A, de Luis EV, Martín-Gayo E, Gaspar ML, de Andrés B, Fernández-Ruiz E. Tyrosine kinase 2 modulates splenic B cells through type I IFN and TLR7 signaling. Cell Mol Life Sci. 2024 Apr 29;81(1):199. 10.1007/s00018-024-05234-y 1420-9071 Cellular and molecular life sciences : CMLS 38683377 http://hdl.handle.net/20.500.12105/19934 Tyrosine kinase 2 modulates splenic B cells through type I IFN and TLR7 signaling