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Enhanced Expression of Bruton's Tyrosine Kinase in B Cells Drives Systemic Autoimmunity by Disrupting T Cell Homeostasis.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2016 Jul 01; Vol. 197 (1), pp. 58-67. Date of Electronic Publication: 2016 May 25. - Publication Year :
- 2016
-
Abstract
- Upon BCR stimulation, naive B cells increase protein levels of the key downstream signaling molecule Bruton's tyrosine kinase (BTK). Transgenic CD19-hBtk mice with B cell-specific BTK overexpression show spontaneous germinal center formation, anti-nuclear autoantibodies, and systemic autoimmunity resembling lupus and Sjögren syndrome. However, it remains unknown how T cells are engaged in this pathology. In this study, we found that CD19-hBtk B cells were high in IL-6 and IL-10 and disrupted T cell homeostasis in vivo. CD19-hBtk B cells promoted IFN-γ production by T cells and expression of the immune-checkpoint protein ICOS on T cells and induced follicular Th cell differentiation. Crosses with CD40L-deficient mice revealed that increased IL-6 production and autoimmune pathology in CD19-hBtk mice was dependent on B-T cell interaction, whereas IL-10 production and IgM autoantibody formation were CD40L independent. Surprisingly, in Btk-overexpressing mice, naive B cells manifested increased CD86 expression, which was dependent on CD40L, suggesting that T cells interact with B cells in a very early stage of immune pathology. These findings indicate that increased BTK-mediated signaling in B cells involves a positive-feedback loop that establishes T cell-propagated autoimmune pathology, making BTK an attractive therapeutic target in autoimmune disease.<br /> (Copyright © 2016 by The American Association of Immunologists, Inc.)
- Subjects :
- Agammaglobulinaemia Tyrosine Kinase
Animals
Antigens, CD19 genetics
Autoimmune Diseases therapy
CD40 Ligand genetics
CD40 Ligand metabolism
Cell Communication
Homeostasis
Humans
Interferon-gamma metabolism
Interleukin-10 metabolism
Interleukin-6 metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Mutation genetics
Promoter Regions, Genetic genetics
Protein-Tyrosine Kinases genetics
Autoimmune Diseases immunology
Autoimmunity
B-Lymphocytes physiology
Protein-Tyrosine Kinases metabolism
T-Lymphocytes immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 197
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 27226091
- Full Text :
- https://doi.org/10.4049/jimmunol.1600208