TY - JOUR
T1 - Btk Supports Autoreactive B Cell Development and Protects against Apoptosis but Is Expendable for Antigen Presentation
AU - Nyhoff, Lindsay E.
AU - Griffith, Amber S.
AU - Clark, Emily S.
AU - Thomas, James W.
AU - Khan, Wasif N.
AU - Kendall, Peggy L.
N1 - Funding Information:
This work was supported by Department of Veterans’ Affairs Merit Award I01 BX 002882 (P.L.K.); by National Institutes of Health Grants: National Institute of Diabetes and Digestive and Kidney Diseases R01 DK084246 (P.L.K.), R01 AI051448-16 (J.W.T.), R01 AI060729 (W.N.K.), P30 A1073961 (E.S.C.), and T32HL069765 (L.E.N.); and by the Jeffrey Modell Foundation (W.N.K.). Flow cytometry experiments were performed in the Vanderbilt University Medical Center Flow Cytometry Shared Resource. The Vanderbilt University Medical Center Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the
Funding Information:
This work was supported by Department of Veterans’ Affairs Merit Award I01 BX 002882 (P.L.K.); by National Institutes of Health Grants: National Institute of Diabetes and Digestive and Kidney Diseases R01 DK084246 (P.L.K.), R01 AI051448-16 (J.W.T.), R01 AI060729 (W.N.K.), P30 A1073961 (E.S.C.), and T32HL069765 (L.E.N.); and by the Jeffrey Modell Foundation (W.N.K.). Flow cytometry experiments were performed in the Vanderbilt University Medical Center Flow Cytometry Shared Resource. The Vanderbilt University Medical Center Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). Btkflox mice were generated at the transgenic core, Miller School of Medicine, University of Miami.
Funding Information:
Flow Cytometry experiments were performed in the Vanderbilt University Medical Center Flow Cytometry Shared Resource. The Vanderbilt University Medical Center Flow Cytometry Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485) and the Vanderbilt Digestive Disease Research Center (DK058404). Btkflox mice were generated at the transgenic core, Miller School of Medicine, University of Miami, Miami, FL.
Publisher Copyright:
© 2021 by The American Association of Immunologists, Inc.
PY - 2021/12/15
Y1 - 2021/12/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85128398878&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.2000558
DO - 10.4049/jimmunol.2000558
M3 - Article
C2 - 34799428
AN - SCOPUS:85128398878
SN - 0022-1767
VL - 207
SP - 2922
EP - 2932
JO - Journal of Immunology
JF - Journal of Immunology
IS - 12
ER -