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Single and dual amino acid substitutions in TCR CDRs can enhance antigen-specific T cell functions.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2008 May 01; Vol. 180 (9), pp. 6116-31. - Publication Year :
- 2008
-
Abstract
- Single and dual amino acid substitution variants were generated in the TCR CDRs of three TCRs that recognize tumor-associated Ags. Substitutions that enhance the reactivity of TCR gene-modified T cells to the cognate Ag complex were identified using a rapid RNA-based transfection system. The screening of a panel of variants of the 1G4 TCR, that recognizes a peptide corresponding to amino acid residues 157-165 of the human cancer testis Ag NY-ESO-1 (SLLMWITQC) in the context of the HLA-A*02 class I allele, resulted in the identification of single and dual CDR3alpha and CDR2beta amino acid substitutions that dramatically enhanced the specific recognition of NY-ESO-1(+)/HLA-A*02(+) tumor cell lines by TCR gene-modified CD4(+) T cells. Within this group of improved TCRs, a dual substitution in the 1G4 TCR CDR3alpha chain was identified that enhanced Ag-specific reactivity in gene-modified CD4(+) and CD8(+) T cells. Separate experiments on two distinct TCRs that recognize the MART-1 27-35 (AAGIGILTV) peptide/HLA-A*02 Ag complex characterized single amino acid substitutions in both TCRs that enhanced CD4(+) T cell Ag-specific reactivity. These results indicate that simple TCR substitution variants that enhance T cell function can be identified by rapid transfection and assay techniques, providing the means for generating potent Ag complex-specific TCR genes for use in the study of T cell interactions and in T cell adoptive immunotherapy.
- Subjects :
- Antigens, Neoplasm genetics
Antigens, Neoplasm immunology
Cell Line, Tumor
Complementarity Determining Regions immunology
HLA-A Antigens genetics
HLA-A2 Antigen
Humans
MART-1 Antigen
Neoplasm Proteins genetics
Neoplasm Proteins immunology
Receptors, Antigen, T-Cell immunology
Amino Acid Substitution immunology
CD4-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes immunology
Complementarity Determining Regions genetics
HLA-A Antigens immunology
Receptors, Antigen, T-Cell genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0022-1767
- Volume :
- 180
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 18424733
- Full Text :
- https://doi.org/10.4049/jimmunol.180.9.6116