RT Journal Article
SR Electronic
T1 Impaired regulatory function of granzyme B-producing B cells against T cell inflammatory responses in lupus mice
JF Lupus Science & Medicine
JO Lupus Sci Med
FD Lupus Foundation of America
SP e000974
DO 10.1136/lupus-2023-000974
VO 10
IS 2
A1 Xue, Jimeng
A1 Xu, Liling
A1 Zhong, Hua
A1 Bai, Mingxin
A1 Li, Xin
A1 Yao, Ranran
A1 Wang, Ziye
A1 Zhao, Zhen
A1 Li, Hongchao
A1 Zhu, Huaqun
A1 Hu, Fanlei
A1 Su, Yin
YR 2023
UL http://lupus.bmj.com/content/10/2/e000974.abstract
AB Objective Recently, 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.Methods GrB 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.Results B 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.Conclusion This 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.Data are available on reasonable request.