REGULATORY MECHANISMS OF IL-5 DEPENDENT IMMUNE REGULATION

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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