H-ferritin (red) binds to TIM-2 (green) and triggers endocytosis of the receptor–ligand pair (yellow).

The TIM (T cell immunoglobulin mucin) proteins have emerged as key regulators of allergic and autoimmune diseases due to their influence on T helper (Th)-1 and Th-2 responses. On page 955, Chen and colleagues show that one member of this family, TIM-2, multitasks as a receptor for H-ferritin, a component of the iron storage protein ferritin.Ferritin was not what the group expected to find when they launched a search for TIM-2 ligands. “Ferritin is not something immunologists think about much,” says senior author William Seaman. Although circulating H-ferritin had been shown to increase during inflammation and to bind to T and B cells, the consequences of these observations were largely unknown.

Chen et al. now show that although TIM-2 is most highly expressed in the liver, the primary iron storage organ, this protein is also found on splenic B cells. TIM-2 expression was particularly high on germinal center B cells that were actively responding to antigenic stimulation. Using a TIM-2 reporter cell line, they showed that a soluble product of activated macrophages bound to TIM-2. That product was H-ferritin. Binding triggered endocytosis of the receptor–ligand pair, suggesting that the interaction was functional.

The authors are now investigating the consequences of the ferritin–TIM-2 interaction. A recent study showed that intracellular H-ferritin is required for the antiapoptotic effect of NF-κB activation in fibroblasts, prompting Seaman to speculate that H-ferritin uptake in activated germinal center B cells might have a similar antiapoptotic effect.