Blood Journal
Leading the way in experimental and clinical research in hematology

TCR affinity and specificity requirements for human regulatory T-cell function

  1. Gabriela Plesa1,*,
  2. Lingjie Zheng1,*,
  3. Andrew Medvec1,
  4. Caleph B. Wilson1,
  5. Camila Robles-Oteiza1,
  6. Nathaniel Liddy2,
  7. Alan D. Bennett2,
  8. Jessie Gavarret2,
  9. Annelise Vuidepot2,
  10. Yangbing Zhao3,
  11. Bruce R. Blazar4,
  12. Bent K. Jakobsen2, and
  13. James L. Riley1
  1. 1Department of Microbiology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
  2. 2Adaptimmune Ltd/ Immunocore Ltd, Abingdon, Oxon, United Kingdom;
  3. 3Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and
  4. 4University of Minnesota Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplant, Minneapolis, MN

Abstract

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-1GAG–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.

  • Submitted September 7, 2011.
  • Accepted January 27, 2012.
View Full Text