K. Bachmaier et al., Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b, NATURE, 403(6766), 2000, pp. 211-216
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.