Regulation of B cell homeostasis by Ptpn22 contributes to type 1 diabetes in NOD mice
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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.
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.
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.
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.
KeywordsType 1 diabetes PTPN22 B cells Autoimmunity
Type 1 diabetes
Regulatory B cells
B cell receptor
Non obese diabetic
Plasmacytoid dendtric cells
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.
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.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants performed by any of the authors. All applicable institutional guidelines for the care and use of animals were followed.
- 8.M.D. Pescovitz, C.J. Greenbaum, H. Krause-Steinrauf, D.J. Becker, S.E. Gitelman, R. Goland, P.A. Gottlieb, J.B. Marks, P.F. McGee, A.M. Moran, P. Raskin, H. Rodriguez, D.A. Schatz, D. Wherrett, D.M. Wilson, J.M. Lachin, J.S. Skyler, Type 1 diabetes Trialnet anti-CD20 Study Group, rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N. Engl. J. Med. 361, 2143–2152 (2009)CrossRefGoogle Scholar
- 9.M.D. Pescovitz, C.J. Greenbaum, B. Bundy, D.J. Becker, S.E. Gitelman, R. Goland, P.A. Gottlieb, J.B. Marks, A. Moran, P. Raskin, H. Rodriguez, D.A. Schatz, D.K. Wherrett, D.M. Wilson, J.P. Krischer, J.S. Skyler, Type 1 diabetes TrialNet Anti-CD20 Study Group, B-lymphocyte depletion with rituximab and beta-cell function: two-year results. Diabetes Care 37, 453–459 (2014)CrossRefGoogle Scholar
- 10.D.V. Serreze, H.D. Chapman, D.S. Varnum, M.S. Hanson, P.C. Reifsnyder, S.D. Richard, S.A. Fleming, E.H. Leiter, L.D. Shultz, B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Ig mu null mice. J. Exp. Med. 184, 2049–2053 (1996)CrossRefGoogle Scholar
- 11.N. Bottini, L. Musumeci, A. Alonso, S. Rahmouni, K. Nika, M. Rostamkhani, J. MacMurray, G.F. Meloni, P. Lucarelli, M. Pellecchia, G.S. Eisenbarth, D. Comings, T. Mustelin, A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36, 337–338 (2004)CrossRefGoogle Scholar
- 14.L. Menard, D. Saadoun, I. Isnardi, Y.S. Ng, G. Meyers, C. Massad, C. Price, C. Abraham, R. Motaghedi, J.H. Buckner, P.K. Gregersen, E. Meffre, The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J. Clin. Investig. 121, 3635–3644 (2011)CrossRefGoogle Scholar
- 15.X. Lin, S. Pelletier, S. Gingras, S. Rigaud, C.J. Maine, K. Marquardt, Y.D. Dai, K. Sauer, A.R. Rodriguez, G. Martin, S. Kupriyanov, L. Jiang, L. Yu, D.R. Green, L.A. Sherman, CRISPR-Cas9-mediated modification of the NOD mouse genome with Ptpn22R619W mutation increases autoimmune diabetes. Diabetes 65, 2134–2138 (2016)CrossRefGoogle Scholar
- 16.T. Habib, A. Funk, M. Rieck, A. Brahmandam, X. Dai, A.K. Panigrahi, E.T. Luning Prak, A. Meyer-Bahlburg, S. Sanda, C. Greenbaum, D.J. Rawlings, J.H. Buckner, Altered B cell homeostasis is associated with type I diabetes and carriers of the PTPN22 allelic variant. J. Immunol. 188, 487–496 (2012)CrossRefGoogle Scholar
- 20.P. Schneider, H. Takatsuka, A. Wilson, F. Mackay, A. Tardivel, S. Lens, T.G. Cachero, D. Finke, F. Beermann, J. Tschopp, Maturation of marginal zone and follicular B cells requires B cell activating factor of the tumor necrosis factor family and is independent of B cell maturation antigen. J. Exp. Med. 194, 1691–1697 (2001)CrossRefGoogle Scholar
- 29.E. Marino, J.L. Richards, K.H. McLeod, D. Stanley, Y.A. Yap, J. Knight, C. McKenzie, J. Kranich, A.C. Oliveira, F.J. Rossello, B. Krishnamurthy, C.M. Nefzger, L. Macia, A. Thorburn, A.G. Baxter, G. Morahan, L.H. Wong, J.M. Polo, R.J. Moore, T.J. Lockett, J.M. Clarke, D.L. Topping, L.C. Harrison, C.R. Mackay, Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes. Nat. Immunol. 18, 552–562 (2017)CrossRefGoogle Scholar