The Journal of Experimental Medicine
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Published online 17 September 2001. doi:10.1084/jem.194.6.719
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© The Rockefeller University Press, 0022-1007/2001/9/719/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 6, September 17, 2001 719-732

Original Article

Anergy in Peripheral Memory Cd4+ T Cells Induced by Low Avidity Engagement of T Cell Receptor

Saied Mirshahidia, Ching-Tai Huangb, and Scheherazade Sadegh-Nasseria

a Department of Pathology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205
b Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD 21205
Ross Bldg./Rm. 664E, 720 Rutland Ave., Baltimore, MD 21205.410-614-3548410-614-4931

ssadegh{at}jhmi.edu

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.

Key Words: T cell tolerance • autoimmunity • transgenic mice • CTLA-4 • antigen presentation

Abbreviations used in this paper: CFA, Complete Freund's Adjuvant; Cyc, cychrome; HA, hemagglutinin; IFA, Incomplete Freund's Adjuvant; Tg, transgenic; PPD, purified protein derivative.

A portion of this paper was presented as a poster in Immunology 2000 in Seattle, WA on May 12–16, 2000.

© 2001 The Rockefeller University Press


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