Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b.
The signalling thresholds of antigen receptors and co-stimulatory receptors determine immunity or tolerance to self molecules. Changes in co-stimulatory pathways can lead to enhanced activation of lymphocytes and autoimmunity, or the induction of clonal anergy. The molecular mechanisms that maintain immunotolerance in vivo and integrate co-stimulatory signals with antigen receptor signals in T and B lymphocytes are poorly understood. Members of the Cbl/Sli family of molecular adaptors function downstream from growth factor and antigen receptors. Here we show that gene-targeted mice lacking the adaptor Cbl-b develop spontaneous autoimmunity characterized by auto-antibody production, infiltration of activated T and B lymphocytes into multiple organs, and parenchymal damage. Resting cbl-b(-/-) lymphocytes hyperproliferate upon antigen receptor stimulation, and cbl-b(-/-) T cells display specific hyperproduction of the T-cell growth factor interleukin-2, but not interferon-gamma or tumour necrosis factor-alpha. Mutation of Cbl-b uncouples T-cell proliferation, interleukin-2 production and phosphorylation of the GDP/GTP exchange factor Vav1 from the requirement for CD28 co-stimulation. Cbl-b is thus a key regulator of activation thresholds in mature lymphocytes and immunological tolerance and autoimmunity.
Bachmaier
K
K
Amgen Institute, Department of Medical Biophysics, University of Toronto, Ontario, Canada.
Krawczyk
C
C
Kozieradzki
I
I
Kong
Y Y
YY
Sasaki
T
T
Oliveira-dos-Santos
A
A
Mariathasan
S
S
Bouchard
D
D
Wakeham
A
A
Itie
A
A
Le
J
J
Ohashi
P S
PS
Sarosi
I
I
Nishina
H
H
Lipkowitz
S
S
Penninger
J M
JM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005260:Female; D018390:Gene Targeting; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D050721:Proto-Oncogene Proteins c-cbl; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D017634:Self Tolerance; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D001323:Autoantibodies; D002352:Carrier Proteins; C118387:Cblb protein, mouse; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases