Suboptimal engagement of the T-cell receptor by a variety of peptide-MHC ligands triggers T-cell anergy

T cells recognize antigen via the T-cell receptor (TCR) and produce a spectrum of responses that range from activation to anergy or cell death. The variety of outcomes may be dictated by the strength of the signals transmitted upon cognate recognition of the TCR. The physiological outcome of TCR engagement is determined by several factors, including the avidity of the ligand for TCR, the duration of engagement, and the presence and nature of accessory molecules present on antigen-presenting cells (APCs). In this review, we discuss a model of anergy induced by presentation of low densities of peptide-major histocompatibility complex (MHC) ligand in CD4⁺ T cells and compare it to anergy induced by altered peptide ligands in an effort to identify a unifying mechanism. We suggest that altered peptide ligand (APL) and low densities of agonist ligands induce anergy by engaging less than optimal numbers of TCRs. The physiological impacts of anergy in memory CD4⁺ T cells are discussed.