Abstract
T cells with high-affinity T cell receptors (TCRs) for a foreign peptide–major histocompatibility complex (pMHC) appear to be negatively selected, even though they have never seen the foreign antigen. To examine how this process operates, we used in vitro yeast display to isolate high-affinity TCRs from the T cell clone 2C. The TCRs showed fast on-rates, which were consistent with reduced CDR (complementarity determining region) flexibility, and cross-reactivity with other cognate pMHCs. T cell hybridomas transfected with a high-affinity TCR were stimulated by endogenous self-pMHC, which suggested that T cells bearing the TCR would be negatively selected. The immune system appears to maintain a repertoire of flexible, low-affinity TCRs at the expense of more effective high-affinity TCRs.
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Acknowledgements
We thank S. Jameson and M. Daniels for the Kb plasmid and advice on tetramer preparation; the NIH Tetramer facility for several of the initial preparations of pMHC tetramers; I. Wilson and K.D. Wittrup for helpful discussions; and G. Durack and the Biotech Flow Facility for expert technical advice and assistance. Supported by NIH Grant RO1 GM55767.
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Holler, P., Chlewicki, L. & Kranz, D. TCRs with high affinity for foreign pMHC show self-reactivity. Nat Immunol 4, 55–62 (2003). https://doi.org/10.1038/ni863
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DOI: https://doi.org/10.1038/ni863
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