CD44v7 interferes with activation-induced cell death by up-regulation of anti-apoptotic gene expression.

Blockade of CD44v7 was described to cure trinitrobenzene sulfonic acid-induced colitis, a disease not developed by mice with targeted deletion of the CD44v7 exon. There was evidence for a reduction in activation-induced cell death on lamina propria lymphocytes of control as compared with CD44v7-deficient mice. To elucidate the mechanism underlying the relative apoptosis resistance of CD44v7-competent as compared with CD44v7-deficient lymphocytes, T cell activation and induction of apoptosis were analyzed on mesenteric lymph node cells and Peyer's patch lymphocytes of CD44v7-deficient and CD44v4-v7-transgenic mice, which overexpress rat CD44v4-v7 on T lymphocytes. CD44v7 deficiency was characterized by an increase in the percentage of apoptotic cells after stimulation, increased numbers of CD95L- and CD152-positive cells, low levels of the anti-apoptotic proteins Bcl-2 and Bcl-Xl, and decreased phosphorylation of the pro-apoptotic protein BAD. Also, lymphocytes from CD44v4-v7-transgenic mice displayed reduced levels of CD95L, low numbers of apoptotic cells, and constitutively elevated levels of Bcl-Xl. When stimulating lymphocytes by CD3 cross-linking, CD44v7 was not recruited toward the immunological synapse and preferentially associated with the cytoskeletal-linker protein ezrin. Thus, as opposed to the CD44 standard isoform, CD44v7 does not function as an accessory molecule; instead, it supports survival of activated T cells by interfering with activation-induced cell death.