Adaptable TCR avidity thresholds for negative selection |
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Authors: | Stojakovic Milica Salazar-Fontana Laura I Tatari-Calderone Zohreh Badovinac Vladimir P Santori Fabio R Kovalovsky Damian Sant'Angelo Derek Harty John T Vukmanovic Stanislav |
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Institution: | Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010, USA. |
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Abstract: | Central tolerance plays a significant role in preventing autoimmune diseases by eliminating T cells with high and intermediate avidity for self. To determine the manner of setting the threshold for deletion, we created a unique transgenic mouse strain with a diverse T cell population and globally increased TCR avidity for self-peptide/MHC complexes. Despite the adaptations aimed at reducing T cell reactivity (reduced TCR levels and increased levels of TCR signaling inhibitor CD5), transgenic mice displayed more severe experimental allergic encephalomyelitis and lupus. The numbers and activity of natural (CD4(+)CD25(+)) regulatory T cells were not altered. These findings demonstrate that the threshold for deletion is adaptable, allowing survival of T cells with higher avidity when TCR avidity is globally increased. |
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