Abstract

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 (Tfh) cells expansion in models of T-dependent immunization and autoimmunity. Mechanistically, CaMK4 controls the Tfh-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 Tfh 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 Tfh cells correlated with those of BCL6. In conclusion, we identify CaMK4/CREMα as a driver of T cell-dependent B cell dysregulation in autoimmunity.

Calmodulin-dependent kinase 4 (CaMK4) has been implicated in humoral immunity. Here, the authors demonstrate that CaMK4 expression controls the differentiation of T follicular helper cells, leading to the expansion of pathogenic B cells in systemic lupus erythematosus.

Details

Title
CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses
Author
Scherlinger, Marc 1   VIAFID ORCID Logo  ; Li, Hao 2   VIAFID ORCID Logo  ; Pan, Wenliang 2 ; Li, Wei 2 ; Karino, Kohei 2   VIAFID ORCID Logo  ; Vichos, Theodoros 2   VIAFID ORCID Logo  ; Boulougoura, Afroditi 2 ; Yoshida, Nobuya 2 ; Tsokos, Maria G. 2   VIAFID ORCID Logo  ; Tsokos, George C. 2   VIAFID ORCID Logo 

 Beth Israel Deaconess Medical Center, Department of Medicine, Boston, USA (GRID:grid.239395.7) (ISNI:0000 0000 9011 8547); Strasbourg University Hospital of Hautepierre, Rheumatology department, Strasbourg, France (GRID:grid.11843.3f) (ISNI:0000 0001 2157 9291); Laboratoire d’ImmunoRhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR_S 1109, Strasbourg, France (GRID:grid.11843.3f) 
 Beth Israel Deaconess Medical Center, Department of Medicine, Boston, USA (GRID:grid.239395.7) (ISNI:0000 0000 9011 8547) 
Pages
840
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2919772514
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.