NDLI: Class II-restricted T cell receptor engineered in vitro for higher affinity retains peptide specificity and function

Content Provider	PubMed Central
Author	Weber, K. Scott Donermeyer, David L. Allen, Paul M. Kranz, David M.
Copyright Year	2005
Abstract	The T cell receptor (TCR) αβ heterodimer determines the peptide and MHC specificity of a T cell. It has been proposed that in vivo selection processes maintain low TCR affinities because T cells with higher-affinity TCRs would (i) have reduced functional capacity or (ii) cross-react with self-peptides resulting in clonal deletion. We used the class II-restricted T cell clone 3.L2, specific for murine hemoglobin (Hb/I-Ek), to explore these possibilities by engineering higher-affinity TCR mutants. A 3.L2 single-chain TCR (Vβ-linker-Vα) was mutagenized and selected for thermal stability and surface expression in a yeast display system. Stabilized mutants were used to generate a library with CDR3 mutations that were selected with Hb/I-Ek to isolate a panel of affinity mutants with K D values as low as 25 nM. Kinetic analysis of soluble single-chain TCRs showed that increased affinities were the result of both faster on-rates and slower off-rates. T cells transfected with the mutant TCRs and wild-type TCR responded to similar concentrations of peptide, indicating that the increased affinity was not detrimental to T cell activation. T cell transfectants maintained exquisite hemoglobin peptide specificity, but an altered peptide ligand that acted as an antagonist for the wild-type TCR was converted to a strong agonist with higher-affinity TCRs. These results show that T cells with high-affinity class II reactive TCRs are functional, but there is an affinity threshold above which an increase in affinity does not result in significant enhancement of T cell activation.
Related Links	http://dx.doi.org/10.1073/pnas.0507554102
Ending Page	19038
Page Count	6
Starting Page	19033
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	52
Volume Number	102
Language	English
Publisher	National Academy of Sciences
Publisher Date	2005-12-27
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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