CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses.

Autor: Scherlinger M; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. marc.scherlinger@chru-strasbourg.fr.; Rheumatology department, Strasbourg University Hospital of Hautepierre, Strasbourg, France. marc.scherlinger@chru-strasbourg.fr.; Laboratoire d'ImmunoRhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1109, Strasbourg, France. marc.scherlinger@chru-strasbourg.fr., Li H; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA., Pan W; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA., Li W; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA., Karino K; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA., Vichos T; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA., Boulougoura A; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA., Yoshida N; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA., Tsokos MG; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA., Tsokos GC; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. gtsokos@bidmc.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jan 29; Vol. 15 (1), pp. 840. Date of Electronic Publication: 2024 Jan 29.
DOI: 10.1038/s41467-024-45080-x
Abstrakt: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell compartment responsible for the production of autoantibodies. Here, we show that T cell-specific expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) leads to T follicular helper (T fh ) cells expansion in models of T-dependent immunization and autoimmunity. Mechanistically, CaMK4 controls the T fh -specific transcription factor B cell lymphoma 6 (Bcl6) at the transcriptional level through the cAMP responsive element modulator α (CREMα). In the absence of CaMK4 in T cells, germinal center formation and humoral immunity is impaired in immunized mice, resulting in reduced anti-dsDNA titres, as well as IgG and complement kidney deposition in the lupus-prone B6.lpr mouse. In human T fh cells, CaMK4 inhibition reduced BCL6 expression and IL-21 secretion ex vivo, resulting in impaired plasmablast formation and IgG production. In patients with SLE, CAMK4 mRNA levels in T fh cells correlated with those of BCL6. In conclusion, we identify CaMK4/CREMα as a driver of T cell-dependent B cell dysregulation in autoimmunity.
(© 2024. The Author(s).)
Databáze: MEDLINE
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