Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells.
Stimulation of T cells via the antigen and costimulatory receptors leads to the organization of a supramolecular activation cluster called the immune synapse. We report that loss of the molecular adaptor Cbl-b in T cells frees antigen receptor-triggered receptor clustering, lipid raft aggregation, and sustained tyrosine phosphorylation from the requirement for CD28 costimulation. Introduction of the cbl-b mutation into a vav1-/- background relieved the functional defects of vav1-/- T cells and caused spontaneous autoimmunity. Wiscott Aldrich Syndrome protein (WASP) was found to be essential for deregulated proliferation and membrane receptor reorganization of cbl-b mutant T cells. Antigen receptor-triggered Ca2+ mobilization, cytokine production, and receptor clustering can be genetically uncoupled in cbl-b mutant T cells. Thus, Cbl-b functions as a negative regulator of receptor clustering and raft aggregation in T cells.
Krawczyk
C
C
Amgen Institute, Toronto, Ontario, Canada.
Bachmaier
K
K
Sasaki
T
T
Jones
R G
RG
Snapper
S B
SB
Bouchard
D
D
Kozieradzki
I
I
Ohashi
P S
PS
Alt
F W
FW
Penninger
J M
JM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics; D020013:Calcium Signaling / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005816:Genetic Complementation Test; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D008232:Lymphoproliferative Disorders / Q000235:genetics; D021962:Membrane Microdomains / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl; D051567:Proto-Oncogene Proteins c-vav; D011940:Receptor Aggregation / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000276:immunology; D051316:Wiskott-Aldrich Syndrome Protein; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C118387:Cblb protein, mouse; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; C496618:VAV1 protein, human; C496619:Vav1 protein, mouse; C495767:WAS protein, human; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D014443:Tyrosine; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D020764:cdc42 GTP-Binding Protein