Btk Supports Autoreactive B Cell Development and Protects against Apoptosis but Is Expendable for Antigen Presentation
| Autor: | Emily S. Clark, James W. Thomas, Wasif N. Khan, Lindsay E. Nyhoff, Amber S Griffith, Peggy L. Kendall |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Immunology
Antigen presentation Syk Receptors Antigen B-Cell Apoptosis Article Downregulation and upregulation immune system diseases hemic and lymphatic diseases medicine Agammaglobulinaemia Tyrosine Kinase Immunology and Allergy Bruton's tyrosine kinase Humans Insulin B cell Antigen Presentation B-Lymphocytes biology CD22 Protein-Tyrosine Kinases medicine.anatomical_structure biology.protein Cancer research Central tolerance Tyrosine kinase |
| Zdroj: | J Immunol |
| ISSN: | 1550-6606 |
| Popis: | Bruton’s tyrosine kinase (Btk) propagates B cell signaling, and BTK inhibitors are in clinical trials for autoimmune disease. Although autoreactive B cells fail to develop in the absence of Btk, its role in mature cells is unknown. To address this issue, a model of conditional removal (Btkflox/Cre-ERT2) was used to excise Btk from mature transgenic B cells that recognize the pathophysiologic autoantigen insulin. Anti-insulin B cells escape central tolerance and promote autoimmune diabetes, mimicking human autoreactive cells. Lifelong Btk deficiency was previously shown to eliminate 95% of anti-insulin B cells, but in this model, mature anti-insulin B cells survived for weeks after targeted Btk deletion, even when competing with a polyclonal repertoire. BCR-stimulated cells could still signal via Syk, PLCy2, and CD22, but failed to upregulate the antiapoptotic protein Bcl-xL, and proliferation was impaired. Surprisingly, Btk-depleted anti-insulin B cells could still present Ag and activate T cells, a critical function in promoting T cell–mediated islet cell destruction. Thus, pharmacologic targeting of Btk may be most effective by blocking expansion of established autoreactive cells, and preventing emergence of new ones. |
| Databáze: | OpenAIRE |
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