Impaired regulatory function of granzyme B-producing B cells against T cell inflammatory responses in lupus mice.
Impaired regulatory function of granzyme B-producing B cells against T cell inflammatory responses in lupus mice.
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DOI：
10.1136/lupus-2023-000974
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发表时间：
2023-07
影响因子：
3.9
通讯作者：
中科院分区：
文献类型：
--
作者：
最近，一种新的产生颗粒酶B(GRB)的Breg细胞亚型被发现，它被证明与自身免疫性疾病有关。我们最近的报道表明，产生GRB的Breg细胞与SLE的临床和免疫学特征有关。然而，产生GRB的Breg细胞在狼疮小鼠中的作用尚不清楚。用流式细胞仪、聚合酶链式反应、酶联免疫吸附试验和ELISpot方法分析GRb在幼稚和狼疮小鼠B细胞中的表达。为了研究产生GRB的B细胞在狼疮模型中的作用，将GRB基因敲除(KO)小鼠和野生型(WT)小鼠分别注射突变小鼠B6.C-H-2bm12(Bm12)的单抗细胞2周。此外，通过B细胞-CD_4+CD_(25)−T细胞与B细胞的G_(RB)阻断/KO体外共培养实验，进一步探讨了B细胞在幼稚和狼疮小鼠中产生G_(Rb)的功能。WT C57BL/6(B6)小鼠脾B细胞能表达并分泌GrB(p<；0.001)。WT小鼠产生GrB的BREG细胞对CD_4+CD_(25)−T细胞具有调节功能。而狼疮小鼠产生GRB的BREG细胞频率显著降低(p=0.001)(p<；0.001)。此外，狼疮小鼠中产生Grb的Breg细胞未能抑制T细胞介导的促炎反应，部分原因是下调T细胞受体-Zeta链和诱导CD_4+CD_(25)−T细胞凋亡的能力受损。本研究进一步揭示了产生GRB的Breg细胞在调节狼疮小鼠T细胞稳态中的作用和机制，并强调了产生GRB的Breg细胞是SLE的治疗靶点。
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. 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. 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. 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.
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