Shimon Sakaguchi

Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan

Title: T cell signaling, regulatory T cells and self-tolerance

Abstract:

Genetically altered signal transduction in T cells can evoke autoimmune disease. SKG mice, a ZAP-70 gene mutant, spontaneously develop autoimmune arthritis. The mutation facilitates degradation of the ZAP-70 protein and impairs its tyrosine-phosphorylation upon TCR stimulation. The attenuated TCR signal transduction lowers the sensitivity of developing T cells to thymic selection, allowing only T cells with highly self-reactive TCRs to be positively selected. Accordingly, depletion of Foxp3+ regulatory T cells (Tregs) from SKG mice enhances arthritis development and de novo produces other autoimmune diseases, whereas it fails to evoke some other autoimmune diseases that are easily induced in ZAP-70-intact mice by Treg depletion. In diabetes-prone NOD mice, the mutation elicits arthritis but inhibits diabetes. The mutation also affects the repertoire and suppressive function of natural Tregs. Thus, genetic alteration in TCR proximal signaling can concurrently modulate both thymic production and Treg-mediated control of self-reactive T cells, promoting some autoimmune diseases while suppressing others. We further show that quantitative change in signal intensity through ZAP-70 affects at every gradation the sensitivity of developing T cells to thymic selection by endogenous self-peptide/MHC. The resulting T cell anomalies range from total T cell-deficiency due to no positive selection of T cells, to the development of T cell-mediated autoimmunity because of enhanced positive selection and impaired negative selection of aberrant self-reactive T cells together with developmental and functional alteration of natural Tregs.

Biography:

My main interest is in the mechanism of immune tolerance. I have been studying the roles of immunosuppressive regulatory T cells in immunological self-tolerance and immune homeostasis for many years since late 1970’s. Immunologists have been skeptical until recently about the existence of such cells. Yet the study of regulatory T cells is now one of the main issues of immunology. We have contributed to this move by showing that self-tolerance can be breached by removing a particular T cell subpopulation, and that such a naturally occurring regulatory population expresses CD25 as a cell surface marker and the transcription factor Foxp3. Our current interest is in how T cell signaling controls the development and function of regulatory T cells and conventional T cells. We are also making attempts to apply regulatory T cells to treat immunological diseases and control physiological and pathological immune responses in clinical settings.