In vivo CD44-CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance.
CD44 is involved in leukocyte migration and activation and has recently been reported to contribute to leukocyte extravasation by associating with CD49d. We explored whether similar changes in CD44 activity are seen in vivo using murine alopecia areata (AA) as a chronic, organ-related autoimmune disease model system. Expression of the activated, hyaluronan-binding form of CD44, and of CD49d, was elevated in draining lymph node cells (LNC) of AA-affected mice as compared to control mice. LNC of AA mice displayed increased motility, proliferative activity and apoptosis resistance, which were equally well inhibited by anti-CD44 and anti-CD49d. The latter is the sequelae of the association between CD44 and CD49d that is seen in activated lymphocytes. Significantly, due to CD44-CD49d complex formation, CD44 gains access to focal adhesion kinase and CD49d gains access to CD44-associated lck and ezrin, such that downstream kinases become activated via CD44 or CD49d engagement. Thus, by their association, CD44 and CD49d mutually avail themselves of the partner's signaling pathways and the ligand binding of each one triggers signaling pathways of both. This strongly influences the lymphocytes' activation state and function.
Marhaba
Rachid
R
Department of Tumor Progression and Immune Defense, German Cancer Research Center, Heidelberg, Germany. r.marhaba@dkfz.de
Freyschmidt-Paul
Pia
P
Zöller
Margot
M
D000506:Alopecia Areata / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000032:analysis / Q000378:metabolism*; D039441:Integrin alpha4 / Q000032:analysis / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008809:Mice, Inbred C3H; D010766:Phosphorylation; D012867:Skin / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D000099149:Ezrin
D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D051417:Focal Adhesion Kinase 1; D018960:Hyaluronan Receptors; D039441:Integrin alpha4; D000099149:Ezrin; C496051:Ptk2 protein, mouse