EXPRESSION AND MODULATION OF CD44 VARIANT ISOFORMS IN HUMANS

CD44 is a ubiquitous surface molecule that exists as a number of isofo rms, generated by alternative splicing of 10 ''variant'' exons. Little is known about the expression and function of the variant isoforms, e xcept that certain isoforms may play a role in cancer metastasis. We p roduced mAbs against CD44 variant regions encoded by exons 4v, 6v, and 9v, by immunizing mice with a fusion protein spanning variant exons 3 v to 10v. A comprehensive analysis of human tissues revealed that CD44 variant isoforms were expressed widely throughout the body, principal ly by epithelial cells. However there was differential expression of C D44 variant exons by different epithelia. Most epithelia expressed exo n 9v, but much fewer expressed 6v or 4v. The regions of epithelia that expressed the highest levels of the variant isoforms were the generat ive cells, particularly the basal cells of stratified squamous epithel ium, and of glandular epithelium. CD44 variant isoforms were also expr essed differentially by leukocytes, with CD44-9v expressed at very low levels and CD44-6v and 4v virtually absent. However, CD44-9v and CD44 -6v were the main variants that were transiently upregulated on T cell s after mitogenic stimulation and on myelomonocytic cell lines by TNFa lpha and IFN-gamma treatment. Some epithelial cell lines could prefere ntially upregulate CD44-6v upon IFNgamma incubation. These results sho w that CD44 variant isoforms are expressed much more widely than first appreciated, and that expression of the variant isoforms on some cell types can be modulated by particular cytokines.