Peripheral CD8+ T Cell Tolerance to Self-Proteins Is Regulated Proximally at the T Cell Receptor

Ryan M. Teague, Philip D. Greenberg, Carla Fowler, Maria Z. Huang, Xiaoxia Tan, Junko Morimoto, Michelle L L. Dossett, Eric S. Huseby, Claes Öhlén

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

CD8+ T cell tolerance, although essential for preventing autoimmunity, poses substantial obstacles to eliciting immune responses to tumor antigens, which are generally overexpressed normal proteins. Development of effective strategies to overcome tolerance for clinical applications would benefit from elucidation of the immunologic mechanism(s) regulating T cell tolerance to self. To examine how tolerance is maintained in vivo, we engineered dual-T cell receptor (TCR) transgenic mice in which CD8+ T cells recognize two distinct antigens: a foreign viral-protein and a tolerizing self-tumor protein. Encounter with peripheral self-antigen rendered dual-TCR T cells tolerant to self, but these cells responded normally through the virus-specific TCR. Moreover, proliferation induced by virus rescued function of tolerized self-tumor-reactive TCR, restoring anti-tumor activity. These studies demonstrate that peripheral CD8+ T cell tolerance to self-proteins can be regulated at the level of the self-reactive TCR complex rather than by central cellular inactivation and suggest an alternate strategy to enhance adoptive T cell immunotherapy.

Original languageEnglish (US)
Pages (from-to)662-674
Number of pages13
JournalImmunity
Volume28
Issue number5
DOIs
StatePublished - May 16 2008
Externally publishedYes

Keywords

  • CELLIMMUNO
  • MOLIMMUNO

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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