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.
Marhaba
Rachid
R
Department of Tumor Progression and Tumor Defense, German Cancer Research Center, Heidelberg, Germany.
Bourouba
Mehdi
M
Zöller
Margot
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D018960:Hyaluronan Receptors / Q000032:analysis / Q000502:physiology*; D008213:Lymphocyte Activation; D021962:Membrane Microdomains; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D051818:Replication Protein C; D013601:T-Lymphocytes / Q000378:metabolism; D015854:Up-Regulation; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; C476399:Cd44 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D051818:Replication Protein C