Hidehiro Kishimoto

A defect in central tolerance in NOD mice

The predisposition of nonobese diabetic (NOD) mice to develop autoimmune disease is usually attributed to defects in peripheral tolerance mechanisms. Here, evidence is presented that NOD mice display a defect in central tolerance (negative selection) of thymocytes. Impaired central tolerance in NOD mice was most prominent in a population of semi-mature thymocytes found in the medulla. The defect was apparent in vivo as well as in vitro, was independent of IAβg7 expression and affected both Fas-dependent and Fas-independent pathways of apoptosis; for Fas-dependent apoptosis, the defective tolerance of NOD thymocytes correlated with the strong T cell receptor–mediated up-regulation of caspase 8–homologous FLICE (Fas-associated death-domain-like interleukin 1β–converting enzyme)-inhibitory protein. In light of these findings, disease onset in NOD mice may reflect defects in central as well as peripheral tolerance.

The thymus and negative selection.

Summary: Maintenance of tolerance to self antigens is presumed to reflect a combination of central and peripheral tolerance. For T cells, central tolerance occurs during early T cell development in the thymus and causes cells with strong reactivity to self antigens to be destroyed in situ (negative selection). Here, we summarize evidence that negative selection can occur in the thymic medulla and affects a population of semimature HSA+ T cells. The influence of costimulatory molecules, Fas and cytokines on negative selection is discussed.

Signaling T‐Cell Survival and Death by IL‐2 and IL‐15

Interleukin 2 (IL‐2) and interleukin 15 (IL‐15) bind to common T‐cell surface receptors comprised of unique alpha (IL‐2Rα or IL‐15Rα) and shared β/γ chain subunits. Ligation of this receptor by IL‐2 can lead to apoptosis whereas IL‐15 ligation favors cell survival. Our study examined intra‐cellular signaling events associated with IL‐2‐ and IL‐15‐induced apoptosis and survival in human T cells. We found IL‐2 and IL‐15 could both induce apoptosis and survival; the outcome depended on cytokine concentration. No qualitative differences in Jak/Stat, Ras/MAPK or PI3K/AKT signaling were seen over a wide range of IL‐2 and IL‐15 concentrations. These findings suggest that, like T‐cell receptor signaling, IL‐2R β/γ chain signaling is regulated, or “tuned,” by the concentration of cytokine.

THE THYMUS AND T CELL DEATH

Through the combined effects of positive and negative selection, T cell differentiation in the thymus generates a repertoire of mature T cells that is tailored to tolerate self antigens but mount strong responses to foreign antigens1,2. Thymic selection is associated with extensive cell death, and only a very small proportion of thymocytes are selected for survival and export to the extrathymic environment. This article provides an overview of thymic selection and the fate of thymocytes.

Response to 'Efficient T cell receptor–mediated apoptosis in nonobese diabetic mouse thymocytes'

Response to Efficient T cell receptor–mediated apoptosis in nonobese diabetic mouse thymocytes