Anergy in peripheral memory CD4+ T cells induced by low avidity engagement of T cell receptor

S. Mirshahidi, C. Huang, S. Sadegh-Nasseri

Research output: Contribution to journalArticlepeer-review


Induction of tolerance in self-reactive memory T cells is an important process in the prevention of autoimmune responses against peripheral self-antigens in autoimmune diseases. Although naive T cells can readily be tolerized, memory T cells are less susceptible to tolerance induction. Recently, we demonstrated that low avidity engagement of T cell receptor (TCR) by low densities of agonist peptides induced anergy in T cell clones. Since memory T cells are more responsive to lower antigenic stimulation, we hypothesized that a low avidity TCR engagement may induce tolerance in memory T cells. We have explored two antigenic systems in two transgenic mouse models, and have tracked specific T cells that are primed and show memory phenotype. We demonstrate that memory CD4+ T cells can be rendered anergic by presentation of low densities of agonist peptide-major histocompatibility complex complexes in vivo. We rule out other commonly accepted mechanisms for induction of T cell tolerance in vivo, such as deletion, ignorance, or immunosuppression. Anergy is the most likely mechanism because addition of interleukin 2-reversed anergy in specific T cells. Moreover, cytotoxic T lymphocyte antigen (CTLA)-4 plays a critical role in the induction of anergy because we observed that there was increased surface expression of CTLA-4 on anergized T cells, and that injection of anti-CTLA-4 blocking antibody restored anergy in vivo.

Original languageEnglish (US)
Pages (from-to)719-731
Number of pages13
JournalJournal of Experimental Medicine
Issue number6
StatePublished - Sep 17 2001
Externally publishedYes


  • Antigen presentation
  • Autoimmunity
  • CTLA-4
  • T cell tolerance
  • Transgenic mice

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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