CD28 as a molecular amplifier extending TCR ligation and signaling capabilities.
Evidence has gathered that CD28 costimulation facilitates T cell activation by potentiating TCR intrinsic-signaling. However, the underlying molecular mechanism is largely unknown. Here we show that, by enhancing T cell/APC close contacts, CD28 facilitates TCR signal transduction. Moreover, the signal supplied by CD28 does not lead to increased Zap-70 and Lat phosphorylation, but amplifies PLCgamma1 activation and Ca(2+) response. We provide evidence that the PTK Itk controls the latter function. Our data suggest that CD28 binding to B7 contributes to setting the level of TCR-induced phosphorylated Lat for recruiting signaling complexes, whereas the CD28 signal boosts multiple pathways by facilitating PLCgamma1 activation. These results should provide a conceptual framework for understanding quantitative and qualitative aspects of CD28-mediated costimulation.
Michel
F
F
Molecular Immunology Unit, Department of Immunology, Institut Pasteur, Paris, France.
Attal-Bonnefoy
G
G
Mangino
G
G
Mise-Omata
S
S
Acuto
O
O
D048868:Adaptor Proteins, Signal Transducing; D000938:Antigen-Presenting Cells / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology; D018106:CD28 Antigens / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D007527:Isoenzymes / Q000378:metabolism; D019169:Jurkat Cells / Q000276:immunology; D008213:Lymphocyte Activation / Q000502:physiology*; D046911:Macromolecular Substances; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000737:chemistry; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
D048868:Adaptor Proteins, Signal Transducing; D018122:B7-1 Antigen; D018106:CD28 Antigens; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D007527:Isoenzymes; C110810:LAT protein, human; D046911:Macromolecular Substances; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D019000:Phosphotyrosine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C080813:emt protein-tyrosine kinase; D010738:Type C Phospholipases; D051966:Phospholipase C gamma