TCR-dependent cell response is modulated by the timing of CD43 engagement.
Binding of Ag by the Ag receptor in combination with other stimuli provided by costimulatory receptors triggers the expansion and differentiation of T lymphocytes. However, it is unclear whether the time when costimulatory molecules interact with their counterreceptors with regards to Ag recognition leads to different T cell responses. Provided that the coreceptor molecule CD43 is a very abundant molecule evenly distributed on the membrane of T cell surface protruding 45 nm from the cell, we hypothesized that CD43 is one of the first molecules that interacts with the APC and thus modulates TCR activation. We show that engaging CD43 before or simultaneously with the TCR inhibited Lck-Src homology 2 domain containing phosphatase-1 interaction, preventing the onset of a negative feedback loop on TCR signals, favoring high levels of IL-2, cell proliferation, and secretion of proinflammatory cytokines and chemokines. In contrast, the intracellular signals resulting of engaging the TCR before CD43 were insufficient to induce IL-2 production and cell proliferation. Interestingly, when stimulated through the TCR and CD28, cells proliferated vigorously, independent of the order with which molecules were engaged. These results indicate that CD43 induces a signaling cascade that prolongs the duration of TCR signaling and support the temporal summation model for T cell activation. In addition to the strength and duration of intracellular signals, our data underscore temporality with which certain molecules are engaged as yet another mechanism to fine tune T cell signal quality, and ultimately immune function.
Fierro
Nora A
NA
Instituto de Biotecnología and Posgrado en Ciencias Bioquímicas, Universidad Nacional Autónoma de México, Cuernavaca, Morelos.
Pedraza-Alva
Gustavo
G
Rosenstein
Yvonne
Y
D000328:Adult; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D017635:Clonal Anergy / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D051917:Leukosialin / Q000276:immunology* / Q000378:metabolism* / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D051917:Leukosialin; D008024:Ligands; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D054645:Protein Phosphatase 1; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases