Abstract
ObjectiveRecently, a new subtype of granzyme B (GrB)-producing Breg cells has been identified, which was proven to be involved in autoimmune disease. Our recent report demonstrated that GrB-producing Breg cells were correlated with clinical and immunological features of SLE. However, the effect of GrB-producing Breg cells in lupus mice is unclear.MethodsGrB expression in naïve and lupus mouse B cells was analysed using flow cytometry, PCR, ELISA and ELISpot assays. To study the role of GrB-producing B cells in a lupus model, GrB knockout (KO) and wild-type (WT) mice were intraperitoneally injected with monoclonal cells from the mutant mouse strain B6.C-H-2bm12 (bm12) for 2 weeks. In addition, the function of GrB-producing Breg cells in naïve and lupus mice was further explored using in vitro B cells-CD4+CD25−T cell co-culture assays with GrB blockade/KO of B cells.ResultsB cells from the spleens of WT C57BL/6 (B6) mice could express and secret GrB (p<0.001). GrB-producing Breg cells from WT mice showed their regulatory functions on CD4+CD25−T cell. While the frequency of GrB-producing Breg cells was significantly decreased (p=0.001) in lupus mice (p<0.001). Moreover, GrB-producing Breg cells in lupus mice failed to suppress T cell-mediated proinflammatory responses, partially due to the impaired capacity of downregulating the T cell receptor-zeta chain and inducing CD4+CD25−T cell apoptosis.ConclusionThis study further revealed the function and mechanism of GrB-producing Breg cells in regulating T cell homeostasis in lupus mice and highlighted GrB-producing Breg cells as a therapeutic target in SLE.
Funder
Beijing Nova Program
Beijing Municipal Natural Science Foundation
National Natural Science Foundation of China
Peking University People’s Hospital Research and Development Funds
Peking University Clinical Medicine Plus X-Young Scholars Project
Beijing Science and Technology Planning Project
Subject
Rheumatology,General Medicine
Cited by
1 articles.
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