T-cell reconstitution without T-cell immunopathology in two models of T-cell-mediated tissue destruction

Pablo Penaloza-Macmaster*, David Masopust, Rafi Ahmed

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Antigen-specific T cells play a pivotal role in adaptive immune responses. However, they also contribute to the progression of a variety of diseases including autoimmune disorders, graft rejection and graft-versus-host disease (GVHD). Non-specific immune-ablation treatments compromise the ability of the host to respond to infection, whereas the selective removal of epitope-specific T cells could theoretically ameliorate T-cellmediated pathology while preserving the rest of the host immune function. In this study we investigated whether it is possible to destroy specific unwanted antigen-specific T cells by incubating polyclonal T-cell populations with major histocompatibility complex (MHC) tetramers that are conjugated to the ribosomal-inactivating toxin, saporin. This strategy resulted in a dramatic reduction in the number of targeted antigen (Ag)-specific CD8 T cells with no observable bystander toxicity in vitro. Moreover, in a model of transferable T-cell-dependent neurological disease induced by intracerebral (i.c.) lymphocytic choriomeningitis virus (LCMV) infection, the targeted killing of LCMV-specific CD8 T cells extended the survival of mice or fully prevented their death, depending on the dose of cells transferred. In addition, the tetramer? saporin conjugate also reduced liver damage in a model of donor T-cell-mediated hepatic destruction. These data provide a proof of principle that MHC tetramers could be exploited for the elimination or clinical manipulation of T-cell responses by linking effector molecules (a toxin in this case) to MHC tetramers. Also, the results suggest that it may be feasible to remodel T-cell responses, especially in immunocompromised hosts who receive adoptive cell transfers with many potential alloreactive cells.

Original languageEnglish (US)
Pages (from-to)164-171
Number of pages8
JournalImmunology
Volume128
Issue number2
DOIs
StatePublished - Oct 2009

Keywords

  • Graft-versus-host disease
  • Immunopathology
  • Lymphocytic choriomeningitis virus
  • T cells
  • T-cell receptor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'T-cell reconstitution without T-cell immunopathology in two models of T-cell-mediated tissue destruction'. Together they form a unique fingerprint.

Cite this