Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function.

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State: Public
Version: Author's accepted manuscript
Serval ID
serval:BIB_6F3E1D237CD2
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function.
Journal
Journal of Immunology
Author(s)
Schmid D.A., Irving M.B., Posevitz V., Hebeisen M., Posevitz-Fejfar A., Sarria J.C., Gomez-Eerland R., Thome M., Schumacher T.N., Romero P., Speiser D.E., Zoete V., Michielin O., Rufer N.
ISSN
1550-6606
Publication state
Published
Issued date
2010
Peer-reviewed
Oui
Volume
184
Number
9
Pages
4936-4946
Language
english
Abstract
Protective adaptive immune responses rely on TCR-mediated recognition of Ag-derived peptides presented by self-MHC molecules. However, self-Ag (tumor)-specific TCRs are often of too low affinity to achieve best functionality. To precisely assess the relationship between TCR-peptide-MHC binding parameters and T cell function, we tested a panel of sequence-optimized HLA-A(*)0201/NY-ESO-1(157-165)-specific TCR variants with affinities lying within physiological boundaries to preserve antigenic specificity and avoid cross-reactivity, as well as two outliers (i.e., a very high- and a low-affinity TCR). Primary human CD8 T cells transduced with these TCRs demonstrated robust correlations between binding measurements of TCR affinity and avidity and the biological response of the T cells, such as TCR cell-surface clustering, intracellular signaling, proliferation, and target cell lysis. Strikingly, above a defined TCR-peptide-MHC affinity threshold (K(D) < approximately 5 muM), T cell function could not be further enhanced, revealing a plateau of maximal T cell function, compatible with the notion that multiple TCRs with slightly different affinities participate equally (codominantly) in immune responses. We propose that rational design of improved self-specific TCRs may not need to be optimized beyond a given affinity threshold to achieve both optimal T cell function and avoidance of the unpredictable risk of cross-reactivity.
Keywords
Antigens, Neoplasm/genetics, Antigens, Neoplasm/immunology, CD8-Positive T-Lymphocytes/immunology, CD8-Positive T-Lymphocytes/metabolism, Cell Adhesion/genetics, Cell Adhesion/immunology, Cell Line, Cell Line, Transformed, Cell Line, Tumor, Cells, Cultured, Cytotoxicity, Immunologic/genetics, HLA-A Antigens/genetics, HLA-A Antigens/immunology, Humans, Membrane Proteins/genetics, Membrane Proteins/immunology, Neoplasm Proteins/genetics, Neoplasm Proteins/metabolism, Peptide Fragments/genetics, Peptide Fragments/metabolism, Protein Binding/genetics, Protein Binding/immunology, Receptors, Antigen, T-Cell, alpha-beta/genetics, Receptors, Antigen, T-Cell, alpha-beta/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
25/08/2010 14:12
Last modification date
20/08/2019 15:28
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