title: Distinct isoforms of the CD45 protein-tyrosine phosphatase differentially regulate interleukin 2 secretion and activation signal pathways involving Vav in T cells.
abstract: The CD45 family of transmembrane protein-tyrosine phosphatases plays a crucial role in the regulation of lymphocyte activation by coupling activation signals from antigen receptors to the signal transduction apparatus. Multiple CD45 isoforms, generated through regulated alternative mRNA splicing, differ only in the length and glycosylation of their extracellular domains. Differential distribution of these isoforms defines subsets of T cells having distinct functions and activation requirements. While the requirement for the intracellular protein-tyrosine phosphatase domains has been documented, the physiological role of the extracellular domains remains elusive. Here we report the generation of CD45-antisense transfected Jurkat T cell clones that lack CD45 or have been reconstituted to uniquely express either the smallest, CD45(0), or the largest, CD45(ABC), isoform. These cells exhibited marked isoform-dependent differences in IL-2 production and tyrosine phosphorylation of cellular proteins, including Vav after anti-CD3 stimulation. These results demonstrate that the distinct CD45 extracellular domains differentially regulate T cell receptor-mediated signaling pathways. Furthermore, these findings suggest that alterations in CD45 isoform expression by individual T cells during thymic ontogeny and after antigen exposure in the periphery directly affects the signaling pathways utilized.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06529-8029, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: McKenney
authors.forename: H
authors.initials: H
authors.lastname: Onodera
authors.forename: L
authors.initials: L
authors.lastname: Gorman
authors.forename: T
authors.initials: T
authors.lastname: Mimura
authors.forename: D M
authors.initials: DM
authors.lastname: Rothstein
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav; D011817:Rabbits; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D018797:Cell Cycle Proteins; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; D017493:Leukocyte Common Antigens; D017027:Protein Tyrosine Phosphatases