title: Absence of co-stimulation and not the intensity of TCR signaling is critical for the induction of T cell unresponsiveness in vivo.
abstract: Understanding the mechanisms of T cell activation versus induction of unresponsiveness is of critical importance for the rational modulation of immune responses. Efficient T cell activation is critical for vaccination purposes, while the inhibition of T cell responses is potentially important for the ablation of autoimmune diseases. Modulation of co-stimulation and changing TCR-mediated signaling using altered peptide ligands (APL) have been shown to result in clonal T cell unresponsiveness. This study compares for the first time the efficiency of the two approaches for the induction of CD8+ T cell unresponsiveness in vivo for naive and memory T cells using TCR-transgenic mice. The results demonstrate that inhibition of CD28-mediated co-stimulation in the presence of a strong TCR-mediated signal most efficiently induces T cell unresponsiveness. In contrast, APL that are capable of weak TCR triggering fail to interfere with T cell responsiveness in vivo and are ignored by T cells. Thus, short-term blockage of CD28 during antigenic stimulation rather than the use of APL is the most promising way to actively down-modulate responsiveness of naive CD8+ T cells at least in the particular TCR-transgenic mouse model analyzed in this study.
authors.affiliation: Basel Institute for Immunology, Switzerland. bachmann@bii.ch
authors.forename: M F
authors.initials: MF
authors.lastname: Bachmann
authors.forename: D E
authors.initials: DE
authors.lastname: Speiser
authors.forename: T W
authors.initials: TW
authors.lastname: Mak
authors.forename: P S
authors.initials: PS
authors.lastname: Ohashi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015536:Down-Regulation; D007108:Immune Tolerance; D007156:Immunologic Memory; D066298:In Vitro Techniques; D008024:Ligands; D008213:Lymphocyte Activation; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D008024:Ligands; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins