Functional dissection of the cytoplasmic subregions of the interleukin-5 receptor alpha chain in growth and immunoglobulin G1 switch recombination ofB cells

The interleukin-5 receptor alpha chain (IL-5R alpha) is known to regulate t he development and Function of B cells and eosinophils. Although the functi ons of IL-5R alpha cytoplasmic domain subregions have been studied extensiv ely using cultured cell lines, this approach has limitations when studying the functions of distinct primary B-cell subpopulations and their responsiv eness to IL-5. In the present study, we generated mice on an IL-5R alpha nu ll background, each expressing a mutant form of an IL-5R alpha transgene li gated to a mu enhancer and VH promoter, either lacking the cytoplasmic DC3 region or substituting two proline residues for alanine (ApvA) in the membr ane-proximal ppvp motif of the cytoplasmic domain. The ppvp motif, which me diates activation of JAK2/STAT5 and Btk, also contributes to c-fos, c-jun a nd c-myc expression. IL-5R alpha null mutant mice showed impaired B-1-cell development, reduced serum immunoglobulin G3 (IgG3) and IgM, no IL-5-induce d enhancement of B-cell proliferation and IL-5-induced switch recombination from the mu gene to gamma1 gene; these were not recovered Following the ex pression of the ApvA mutant. In contrast. absence of the DC3 region affecte d the IL-5-induced switch recombination from the CI ro the gamma1 gene and B-1-cell development, while IL-5-induced proliferation and IgM production w ere at levels similar to those of B cells expressing wild-type IL-5R alpha transgene. The results clearly indicated that the ppvp motif and the DC3 re gion of IL-5R alpha played distinct roles in B-cell proliferation and diffe rentiation. Thus, this present approach offers new insights into the functi ons of the cytoplasmic subregions of IL-5R alpha. in particular its carboxy -terminal region.