PMID- 10646608
OWN - NLM
STAT- MEDLINE
DCOM- 20000210
LR  - 20190412
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 403
IP  - 6766
DP  - 2000 Jan 13
TI  - Negative regulation of lymphocyte activation and autoimmunity by the molecular
      adaptor Cbl-b.
PG  - 211-6
AB  - 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.
FAU - Bachmaier, K
AU  - Bachmaier K
AD  - Amgen Institute, Department of Medical Biophysics, University of Toronto,
      Ontario, Canada.
FAU - Krawczyk, C
AU  - Krawczyk C
FAU - Kozieradzki, I
AU  - Kozieradzki I
FAU - Kong, Y Y
AU  - Kong YY
FAU - Sasaki, T
AU  - Sasaki T
FAU - Oliveira-dos-Santos, A
AU  - Oliveira-dos-Santos A
FAU - Mariathasan, S
AU  - Mariathasan S
FAU - Bouchard, D
AU  - Bouchard D
FAU - Wakeham, A
AU  - Wakeham A
FAU - Itie, A
AU  - Itie A
FAU - Le, J
AU  - Le J
FAU - Ohashi, P S
AU  - Ohashi PS
FAU - Sarosi, I
AU  - Sarosi I
FAU - Nishina, H
AU  - Nishina H
FAU - Lipkowitz, S
AU  - Lipkowitz S
FAU - Penninger, J M
AU  - Penninger JM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antigens, CD)
RN  - 0 (Autoantibodies)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cblb protein, mouse)
RN  - 0 (Phosphoproteins)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 42HK56048U (Tyrosine)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-cbl)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
SB  - IM
MH  - *Adaptor Proteins, Signal Transducing
MH  - Animals
MH  - Antigens, CD/biosynthesis
MH  - Autoantibodies/biosynthesis
MH  - Autoimmunity/genetics
MH  - B-Lymphocytes/immunology
MH  - Carrier Proteins/genetics/metabolism/*physiology
MH  - Female
MH  - Gene Targeting
MH  - Lymph Nodes/immunology/pathology
MH  - *Lymphocyte Activation
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phosphoproteins/genetics/metabolism/*physiology
MH  - Phosphorylation
MH  - Proto-Oncogene Proteins c-cbl
MH  - Receptors, Antigen, T-Cell/immunology
MH  - Self Tolerance
MH  - Spleen/immunology/pathology
MH  - T-Lymphocytes/*immunology
MH  - Tyrosine/metabolism
MH  - *Ubiquitin-Protein Ligases
EDAT- 2000/01/26 09:00
MHDA- 2001/03/23 10:01
CRDT- 2000/01/26 09:00
PHST- 2000/01/26 09:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 2000/01/26 09:00 [entrez]
AID - 10.1038/35003228 [doi]
PST - ppublish
SO  - Nature. 2000 Jan 13;403(6766):211-6. doi: 10.1038/35003228.