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

K Bachmaier, C Krawczyk, I Kozieradzki, YY Kong… - Nature, 2000 - nature.com
K Bachmaier, C Krawczyk, I Kozieradzki, YY Kong, T Sasaki, A Oliveira-dos-Santos…
Nature, 2000nature.com
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 …
Abstract
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-γ or tumour necrosis factor-α. 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.
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