ABSTRACT
T-cell receptor affinity for self-antigen has an important role in establishing self-tolerance. Three transgenic mouse strains expressing antigens of variable affinity for the OVA transgenic-I T-cell receptor were generated to address how TCR affinity affects the efficiency of negative selection, the ability to prime an autoimmune response, and the elimination of the relevant target cell. Mice expressing antigens with an affinity just above the negative selection threshold exhibited the highest risk of developing experimental autoimmune diabetes. The data demonstrate that close to the affinity threshold for negative selection, sufficient numbers of self-reactive T cells escape deletion and create an increased risk for the development of autoimmunity.
Subject(s)
Autoantigens/immunology , Autoimmunity/immunology , Receptors, Antigen, T-Cell/immunology , T-Lymphocytes/immunology , Animals , Autoantigens/metabolism , Autoimmunity/genetics , Binding, Competitive/immunology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/metabolism , Flow Cytometry , Insulin-Secreting Cells/immunology , Insulin-Secreting Cells/metabolism , Mice, Inbred C57BL , Mice, Transgenic , Ovalbumin/genetics , Ovalbumin/immunology , Ovalbumin/metabolism , Protein Binding/immunology , Receptors, Antigen, T-Cell/metabolism , Self Tolerance/genetics , Self Tolerance/immunology , T-Lymphocytes/metabolismABSTRACT
The strength of interactions between T cell receptors and the peptide-major histocompatibility complex (pMHC) directly modulates T cell fitness, clonal expansion, and acquisition of effector properties. Here we show that asymmetric T cell division is an important mechanistic link between increased signal strength, effector differentiation, and the ability to induce tissue pathology. Recognition of pMHC above a threshold affinity drove responding T cells into asymmetric cell division. The ensuing proximal daughters underwent extensive division and differentiated into short-lived effector cells expressing the integrin VLA-4, allowing the activated T cell to infiltrate and mediate destruction of peripheral target tissues. In contrast, T cells activated by below-threshold antigens underwent symmetric division, leading to abortive clonal expansion and failure to fully differentiate into tissue-infiltrating effector cells. Antigen affinity and asymmetric division are important factors that regulate fate specification in CD8(+) T cells and predict the potential of a self-reactive T cell to mediate tissue pathology.
