Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b

Citation
K. Bachmaier et al., Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b, NATURE, 403(6766), 2000, pp. 211-216
Citations number
23
Categorie Soggetti
Multidisciplinary,Multidisciplinary,Multidisciplinary
Journal title
NATURE
ISSN journal
00280836 → ACNP
Volume
403
Issue
6766
Year of publication
2000
Pages
211 - 216
Database
ISI
SICI code
0028-0836(20000113)403:6766<211:NROLAA>2.0.ZU;2-P
Abstract
The signalling thresholds of antigen receptors and co-stimulatory receptors determine immunity or tolerance to self molecules(1). Changes in co-stimul atory pathways can lead to enhanced activation of lymphocytes and autoimmun ity, or the induction of clonal anergy(2). The molecular mechanisms that ma intain immunotolerance in vivo and integrate co-stimulatory signals with an tigen receptor signals in T and B lymphocytes are poorly understood. Member s of the Cbl/Sli family of molecular adaptors function downstream from grow th factor and antigen receptors(3-5). 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 in to 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-celI growth factor interleukin-2 , hut not interferon-gamma or tumour necrosis factor-alpha. Mutation of Cbl -b uncouples T-cell proliferation, interleukin-2 production and phosphoryla tion of the GDP/GTP exchange factor Vav1 from the requirement for CD28 cost imulation. Cbl-b is thus a key regulator of activation thresholds in mature lymphocytes and immunological tolerance and autoimmunity.