title: CD45-associated protein promotes the response of primary CD4 T cells to low-potency T-cell receptor (TCR) stimulation and facilitates CD45 association with CD3/TCR and lck.
abstract: Although it is clear that the CD45 tyrosine phosphatase is required for efficient T-cell activation and T-cell development, the factors that regulate CD45 function remain uncertain. Previous data have indicated that there is an association of CD45 with CD4 and the T-cell receptor (TCR) complex controlled by the variable ectodomain of CD45 and, following activation, by high- and low-potency peptides. This suggests that controlling substrate access to CD45 may be an important regulatory mechanism during T-cell activation. In the present study we have examined the role of the transmembrane adapter-like molecule CD45-associated protein (CD45-AP) in regulating the association of CD45 with CD3/TCR and lck, and in regulating primary CD4(+) T-lymphocyte activation. In CD4(+) T cells from CD45-AP-deficient mice, coimmunoprecipitation of CD45 with the CD3/TCR complex, in addition to lck, is significantly reduced compared with wild-type T cells. Functionally, this correlates with a decreased proliferative response, a decrease in interleukin (IL)-2 production, and a decrease in calcium flux upon stimulation with a low-potency altered peptide ligand. However, the response of CD45-AP-deficient T cells to stimulation with a high-avidity agonist peptide was largely intact, except for a modest decrease in IL-2 production. These data suggest that CD45-AP promotes or stabilizes the association of CD45 with substrates and regulates the threshold of T-cell activation.
authors.affiliation: Department of Microbiology, Immunology and Tropical Medicine, George Washington University Medical Center, Washington, DC 20037, USA. dLeit@gwu.edu
authors.forename: David
authors.initials: D
authors.lastname: Leitenberg
authors.forename: Rustom
authors.initials: R
authors.lastname: Falahati
authors.forename: Dan Dan
authors.initials: DD
authors.lastname: Lu
authors.forename: Akiko
authors.initials: A
authors.lastname: Takeda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology; D000818:Animals; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D007376:Interleukin-2 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C513303:Ptprcap protein, mouse; D011948:Receptors, Antigen, T-Cell; C402726:Sh2d2a protein, mouse; D002118:Calcium