Abrogation of experimental colitis correlates with increased apoptosis in mice deficient for CD44 variant exon 7 (CD44v7)

Experimental colitis in mice is characterized by infiltration of activated T helper (Th) cells and macrophages into the lamina propria. Particularly, these cells expressed CD44 variant exon 7 (CD44v7)-containing isoforms. Upr egulation of CD44v7 isoforms was induced by CD40 ligation, an inflammation- driving interaction between activated Th cells and macrophages. To de fine the role of CD44v7 in colitis, mice bearing a targeted deletion for exon v7 were generated. In trinitrobenzene sulfonic acid-induced colitis, wild-typ e mice developed severe signs of persistent inflammation. Mice lacking CD44 v7 initially showed unspecific inflammation, then recovered completely. The pathogenic origin was shown to reside in bone marrow-derived CD44v7(+) cel ls, because adoptive transfer experiments demonstrated an absolute requirem ent for CD44v7 on hematopoietic cells for maintenance of colitis. Interleuk in (IL)-10-deficient mice, which develop a chronic Th1-driven enterocolitis , were crossbred with CD44v6/v7 null mice. In IL-10 x CD44v6/v7 double defi cient mice, intestinal inflammation developed only weakly and at an older a ge. Analysis of cell death in the inflamed lesions revealed that mononuclea r cells in the CD44v7 null infiltrates had higher rates of apoptosis than t hose from wild-type mice. Thus, the region encoded by CD44v7 appears to be essential for survival of effector lymphocytes, resulting in persistence of inflammation.