Antigen-specific immunotolerance limits the expansion of self-reactive T cells involved in autoimmune diseases. Here, we show that the E3 ubiquitin ligase Cbl-b is upregulated in T cells after tolerizing signals. Loss of Cbl-b in mice results in impaired induction of T cell tolerance both in vitro and in vivo. Importantly, rechallenge of Cbl-b mutant mice with the tolerizing antigen results in massive lethality. Moreover, ablation of Cbl-b resulted in exacerbated autoimmunity. Mechanistically, loss of Cbl-b rescues reduced calcium mobilization of anergic T cells, which was attributed to Cbl-b-mediated regulation of PLCgamma-1 phosphorylation. Our results show a critical role for Cbl-b in the regulation of peripheral tolerance and anergy of T cells.

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Background: ␣B-Crystallin is therapeutic in animal models of multiple sclerosis and ischemia. Results: Crystallin binds ϳ70 plasma proteins; over half are members of the acute phase, coagulation, and complement pathways. Conclusion:The heat shock protein can bind with apparent selectivity and modulate inflammation. Significance: The capacity of the heat shock protein to bind a spectrum of ligands represents a unique therapeutic reagent.

There is great variability in platelet transfusion practices among US and Canadian neonatologists, suggesting clinical equipoise in many clinical scenarios. Prospective randomized clinical trials to generate evidence-based neonatal platelet transfusion guidelines are needed.