TCR affinity and specificity requirements for human regulatory T-cell function.
We investigated whether TCRs restricted to the more ubiquitously expressed MHC class I molecules could be used to redirect human regulatory T cells (Tregs). Using a series of HLA-A2-restricted TCRs that recognize the same peptide-MHC class I complex (pMHC) with affinities varying up to 3500 fold, we observed that TCR affinity had no effect on the ability of the introduced TCRs to confer potent Ag-specific suppressive activity. Surprisingly, we found a naturally occurring, low-affinity MHC class I-restricted TCR specific for an NY-ESO-1 epitope that was unable to redirect a functional CD4 T-effector cell response could confer potent antigen-specific suppressive activity when expressed in Tregs and severely impair the expansion of highly functional HIV-1(GAG)-specific CD8 T cells expressing a high-affinity TCR. This suppressive activity was only observed when both Ags were presented by the same cell, and no suppression was observed when the target Ags were put in distinct cells. These studies underscore the clinical utility of using MHC class I-restricted TCRs to endow Tregs with specificity to control autoimmune disease and highlight the conditions in which this approach would have most therapeutic benefit.
Department of Microbiology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6160, USA.
Gabriela
G
Plesa
Lingjie
L
Zheng
Andrew
A
Medvec
Caleph B
CB
Wilson
Camila
C
Robles-Oteiza
Nathaniel
N
Liddy
Alan D
AD
Bennett
Jessie
J
Gavarret
Annelise
A
Vuidepot
Yangbing
Y
Zhao
Bruce R
BR
Blazar
Bent K
BK
Jakobsen
James L
JL
Riley
D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000737:chemistry / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D020014:K562 Cells; D008213:Lymphocyte Activation / Q000235:genetics / Q000502:physiology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology
D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D054301:gag Gene Products, Human Immunodeficiency Virus; D049452:Green Fluorescent Proteins