1. Laboratory of Transplantation Immunology and Nephrology, Department of Research, University Hospital–Basel, Hebelstrasse 20, 4031 Basel, Switzerland
2. Pediatric Immunology, Center for Biomedicine and The University Children's Hospital of Basel, Mattenstrasse 28, 4058 Basel, Switzerland
3. Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
4. Department of Cell Biology & Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, New Jersey 08854-8082, USA

Correspondence to: Ed Palmer¹ Correspondence and requests for materials should be addressed to E.P. (Email: ed.palmer@unibas.ch).

Abstract

A healthy individual can mount an immune response to exogenous pathogens while avoiding an autoimmune attack on normal tissues. The ability to distinguish between self and non-self is called 'immunological tolerance' and, for T lymphocytes, involves the generation of a diverse pool of functional T cells through positive selection and the removal of overtly self-reactive thymocytes by negative selection during T-cell ontogeny. To elucidate how thymocytes arrive at these cell fate decisions, here we have identified ligands that define an extremely narrow gap spanning the threshold that distinguishes positive from negative selection. We show that, at the selection threshold, a small increase in ligand affinity for the T-cell antigen receptor leads to a marked change in the activation and subcellular localization of Ras and mitogen-activated protein kinase (MAPK) signalling intermediates and the induction of negative selection. The ability to compartmentalize signalling molecules differentially in the cell endows the thymocyte with the ability to convert a small change in analogue input (affinity) into a digital output (positive versus negative selection) and provides the basis for establishing central tolerance.

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