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

Induction of tolerance in self-reactive memory T cells is an important proc ess in the prevention of autoimmune responses against peripheral self-antig ens 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 (TCP,) by low d ensities 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 presenta tion of low densities of agonist peptide-major histocompatibility complex c omplexes in vivo. We rule out other commonly accepted mechanisms for induct ion of T cell tolerance in vivo, such as deletion, ignorance, or immunosupp ression. Anergy is the most likely mechanism because addition of interleuki n 2-reversed anergy in specific T cells. Moreover, cytotoxic T lymphocyte a ntigen (CTLA)-4 plays a critical role in the induction of anergy because we observed that there was increased surface expression of CTLA-4 on anergize d T cells, and that injection of anti-CTLA-4 blocking antibody restored ane rgy in vivo.