Abstract
Purpose
A coding variant in PTPN22 (C1858T) is one of the most important genetic risk factors in type 1 diabetes (T1D). The role of the PTPN22 risk allele in B cells is still incompletely understood and has not been investigated directly in T1D. This study aimed to explore the role of PTPN22 in the homeostasis of B cells and its influence in T1D.
Methods
Wild-type (WT) and Ptpn22 inducible knockdown (KD) NOD mice were treated with 200 μg/ml doxycycline at the age of 10 weeks for 1–2 months. B cell compositions in the bone marrow, peritoneal cavity and spleen were examined. The pathogenicity of Ptpn22 KD B cells was explored by adoptive cell transfer.
Results
Ptpn22 silencing increased the frequency of recirculating mature B cells in the bone marrow, decreased the frequency of B-1a cells in the peritoneal cavity and suppressed the formation of marginal zone B cells and plasma cells in the spleen. Changes in the composition of the peripheral B cell compartment caused by altered cell proliferation while rates of apoptosis were not affected. Significantly, co-transfer of Ptpn22 KD B cells with NY8.3 diabetogenic T cells diminished the frequency of diabetes in recipient NOD.scid mice compared with co-transfer of WT B cells.
Conclusions
Our study constitutes the first functional study of Ptpn22 in B cells in NOD mice. Our findings suggest that Ptpn22 variation contributes to T1D by modifying the B cell compartment and support a gain-of-function for the PTPN22 disease variant.
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Abbreviations
- T1D:
-
Type 1 diabetes
- IAA:
-
Anti-insulin antibodies
- Breg:
-
Regulatory B cells
- BCR:
-
B cell receptor
- Dox:
-
Doxycycline
- NOD:
-
Non obese diabetic
- WT:
-
Wild type
- BrdU:
-
Bromodeoxyuridine
- MZ:
-
Marginal zone
- FO:
-
Follicular
- pDC:
-
Plasmacytoid dendtric cells
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Acknowledgements
This work is supported by the National Natural Science Foundation of China (Grant No. 81670716, 81500600), Hunan Natural Science Fund for Excellent Young Scholars (Grant No. 2019JJ30036), and the Graduate innovation project of Central South University (Grant No. 2018zzts921). The authors declare no conflicts of interest.
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All authors have read and approved the final manuscript. P.Z., L.J., and Z.Z. discussed, designed the study and critically edited the manuscript. X.S. and F.S. conducted the experiments, analysed data, and wrote the manuscript. Z.L., L.K., and J.L. contributed to the experiments and discussion. S.K. provided P2 transgenic mice and critically edited the manuscript.
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Shi, X., Shao, F., Li, Z. et al. Regulation of B cell homeostasis by Ptpn22 contributes to type 1 diabetes in NOD mice. Endocrine 67, 535–543 (2020). https://doi.org/10.1007/s12020-019-02120-7
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DOI: https://doi.org/10.1007/s12020-019-02120-7