REGULATORY MECHANISMS OF IL-5 DEPENDENT IMMUNE REGULATION

白细胞介素5 （IL-5）通过与其受体（IL-5R）相互作用诱导B细胞增殖和分化，该受体由两个不同的多肽链α和β(βc)组成。在本项目中，我们试图阐明IL-5在b细胞增殖和分化中的作用。我们发现IL-5/IL-5R系统在维持成熟B-1细胞的数量和细胞大小以及功能方面起着重要作用。野生型（WT）小鼠、T细胞缺失小鼠或肥大细胞缺失小鼠注射抗il -5单抗后，B-1细胞总数和细胞大小的减少程度与IL-5Rα缺失（IL-5Rα^<-/->）小鼠相似。细胞转移实验表明，在缺乏IL-5Rα的情况下，WT小鼠的B-1细胞存活和rag2 ^<-/->小鼠的稳态增殖受到损害。IL-5刺激WT B-1细胞，而不是IL-5Rα ^<-/-> B-1细胞，可以增强CD40的表达，并增加IgM和IgG的产生。在IL-5Rα^<-/->小鼠中，未观察到口服LPS诱导粪便中IgA生成的增强。我们的研究结果阐明了IL-5在成熟B-1细胞的稳态增殖和存活以及粘膜组织中IgA产生中的作用。IL-5刺激cd38激活的小鼠脾B细胞在DNA水平诱导μ-γ - 1类开关重组（CSR），导致高水平的IgG1产生。在系统中进一步添加IL-4可增强il -5依赖性m-g1 CSR。我们在cd38激活的小鼠脾B细胞中检测了IL-5和激活诱导胞苷脱氨酶（AID）对Stat的激活。证实了Stat5a和Stat5b在IL-5诱导的μ-γ - 1 CSR以及IgG1和IgM产生中的作用，因为IL-5不作用于来自Stat5a^<-/->和Stat5b^<-/->小鼠的cd38刺激的脾B细胞。IL-5刺激后，Stat5a^<-/-> /和Stat5b^<-/->/ B细胞中cd38诱导的种系γ - 1转录本和AID的表达水平与WT B细胞相当。Stat5b^<-/-> / B细胞损伤的μ-γ - 1 CSR部分被IL-4修复，而Stat5a^<-/-> / B细胞不被IL-4修复。对WT B细胞分裂周期数的分析表明，在5 ~ 6次细胞分裂后可观察到μ-γ - 1 CSR。Stat5a^<-/-> / B细胞和Stat5b^<-/->/ B细胞表现出相似的细胞分裂周期，但未发生μ-γ - 1 CSR。我们的数据支持Stat5a和Stat5b对于il - s依赖性μ-γ - 1 CSR和Ig分泌至关重要的观点，然而，它们的主要靶点可能不是AID。Stat5a和Stat5b并不是多余的，但至少在功能上是部分不同的。少

Interleukin 5 (IL-5) induces proliferation and differentiation of B cells by interacting with its receptor (IL-5R) which consists of two distinct polypeptide chains, α and β(βc). In this project, we attempted to elucidate the role of IL-5 in B-cell proliferation and differentiation. We found that the IL-5/IL-5R system plays an important role in maintaining the number and the cell size as well as the functions of mature B-1 cells. The administration of anti-IL-5 mAb into wild-type (WT) mice, T -cell-depleted mice or mast cell-depleted mice resulted in reduction in the total number and cell size of B-1 cells to a similar extent to IL-5Rα-deficient (IL-5Rα^<-/->) mice. Cell transfer experiments have demonstrated that B-1 cell survival in WT mice and homeostatic proliferation in RAG-2^<-/-> mice are impaired in the absence of the IL-5Rα. IL-5 stimulation of WT B-1 cells, but not IL-5Rα ^<-/-> B-1 cells, enhances CD40 expression and augments IgM and IgG production following stimulation with … More anti-CD40 mAb. Enhanced IgA production in feces induced by the oral administration of LPS was not observed in IL-5Rα^<-/-> mice. Our results illuminate the role of IL-5 in the homeostatic proliferation and survival of mature B-1 cells and in IgA production in the mucosal tissues.IL-5 stimulation of CD38-activated murine splenic B cells induces μ-γ1 class switch recombination (CSR) at the DNA level leading to a high level of IgG1 production. Further addition of IL-4 in the system enhances IL-5-dependent m-g1 CSR. We examined the activation of Stat by IL-5 and activation-induced cytidine deaminase (AID) in CD38-activated murine splenic B cells. The role of Stat5a and Stat5b in IL-5-induced μ-γ1 CSR and also IgG1 and IgM production was documented, as IL-5 does not act on CD38-stimulated splenic B cells from Stat5a^<-/-> / and Stat5b^<-/-> mice. Expression levels of CD38-induced germline γ1 transcripts and of AID in Stat5a^<-/-> /-and Stat5b^<-/->/ B cells upon IL-5 stimulation were comparable to those of WT B cells. The impaired μ-γ1 CSR by Stat5b^<-/-> B cells, but not by Stat5a^<-/-> / B cells, was rescued in part by IL-4. Analysis of cell division cycle number of WT B cells revealed that μ-γ1 CSR was observed after five to six cell divisions. Stat5a^<-/-> / and Stat5b^<-/->/ B cells showed similar cell division cycles, but they did not undergo μ-γ1 CSR. Our data supports the notion that both Stat5a and Stat5b are essential for IL-S-dependent μ-γ1 CSR and Ig secretion, however, their major target may not be AID. Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function. Less