The rabbit genome has 13 different Calpha genes that are expressed at different levels in mucosal tissues. To analyze the factors involved in the differential expression of these Calpha genes, we cloned and sequenced the promoters of the Ialpha regions that control the expression of sterile mRNA. We found that all Calpha genes, including Calpha3 and Calpha8, which are not expressed, and Calpha4, which is expressed at high levels, have similar nucleotide sequences in the Ialpha region, and all contain the recognition elements for TGF-beta in the promoter. B lymphocytes from popliteal lymph nodes or Peyer's patch activated in vitro could be induced by TGF-beta to express sterile IgA transcripts of all IgA isotypes, except Calpha2, Calpha3, and Calpha8. Many single B lymphocytes transcribed sterile mRNA of more than one IgA isotype, which demonstrates that transcription of sterile mRNA alone does not regulate the IgA isotype switch. The addition of IL-2 led to the expression of transcripts of mature IgA of all isotypes, except Calpha2, Calpha3, and Calpha8. The predominantly expressed isotype in these experiments was Calpha4. With the use of an IgA4-specific mAb we found that IgA4+ plasma cells are unevenly distributed throughout the small intestine such that many of the IgA+ plasma cells in the duodenum-jejunum produced IgA4, whereas in the lower part of the ileum IgA4-producing cells were almost absent. Because the microbial flora varies throughout the intestine, we suggest that the microbial flora creates different local environments and thus affects either isotype switching or homing of IgA-expressing cells.