PMID- 10646609
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  - Cbl-b regulates the CD28 dependence of T-cell activation.
PG  - 216-20
AB  - Whereas co-stimulation of the T-cell antigen receptor (TCR) and CD28 triggers
      T-cell activation, stimulation of the TCR alone may result in an anergic state or
      T-cell deletion, both possible mechanisms of tolerance induction. Here we show
      that T cells that are deficient in the adaptor molecule Cbl-b (ref. 3) do not
      require CD28 engagement for interleukin-2 production, and that the Cbl-b-null
      mutation (Cbl-b(-/-)) fully restores T-cell-dependent antibody responses in
      CD28-/- mice. The main TCR signalling pathways, such as tyrosine kinases Zap-70
      and Lck, Ras/mitogen-activated kinases, phospholipase Cgamma-1 and Ca2+
      mobilization, were not affected in Cbl-b(-/-) T cells. In contrast, the
      activation of Vav, a guanine nucleotide exchange factor for Rac1/Rho/CDC42, was
      significantly enhanced. Our findings indicate that Cbl-b may influence the CD28
      dependence of T-cell activation by selectively suppressing TCR-mediated Vav
      activation. Mice deficient in Cbl-b are highly susceptible to experimental
      autoimmune encephalomyelitis, suggesting that the dysregulation of signalling
      pathways modulated by Cbl-b may also contribute to human autoimmune diseases such
      as multiple sclerosis.
FAU - Chiang, Y J
AU  - Chiang YJ
AD  - Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, 
      National Institutes of Health, Rockville, Maryland 20852, USA.
FAU - Kole, H K
AU  - Kole HK
FAU - Brown, K
AU  - Brown K
FAU - Naramura, M
AU  - Naramura M
FAU - Fukuhara, S
AU  - Fukuhara S
FAU - Hu, R J
AU  - Hu RJ
FAU - Jang, I K
AU  - Jang IK
FAU - Gutkind, J S
AU  - Gutkind JS
FAU - Shevach, E
AU  - Shevach E
FAU - Gu, H
AU  - Gu H
LA  - eng
PT  - Journal Article
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (CD28 Antigens)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cblb protein, mouse)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 0 (Interleukin-2)
RN  - 0 (Phosphoproteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Proto-Oncogene Proteins c-vav)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Vav1 protein, mouse)
RN  - EC 2.3.2.27 (CBLB protein, human)
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  - Autoimmunity
MH  - CD28 Antigens/*immunology
MH  - Carrier Proteins/genetics/metabolism/*physiology
MH  - *Cell Cycle Proteins
MH  - Cell Line
MH  - Gene Targeting
MH  - Guanine Nucleotide Exchange Factors/physiology
MH  - Immune Tolerance
MH  - Interleukin-2/biosynthesis
MH  - Lymphocyte Activation/*physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phosphoproteins/genetics/metabolism/*physiology
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-cbl
MH  - Proto-Oncogene Proteins c-vav
MH  - Receptors, Antigen, T-Cell/metabolism
MH  - Signal Transduction
MH  - T-Lymphocytes/*immunology
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 - 10.1038/35003235 [doi]
PST - ppublish
SO  - Nature. 2000 Jan 13;403(6766):216-20. doi: 10.1038/35003235.