Intravenous injection of soluble antigen induces thymic and peripheral T-cells apoptosis.

Abstract

The mechanism by which tolerance is induced via systemic administration of high doses of aqueous antigen has been analyzed by using mice transgenic for a T-cell receptor specific for the influenza virus hemagglutinin (HA) peptide comprising amino acids 126-138. After intravenous injection of 750 (but not 75) ,ug of HA peptide, a state of hyporesponsiveness was rapidly induced. In the thymus, in situ apoptosis in the cortex and at the corticomedullary junction was responsible for a synchronous and massive deletion of CD4+ CD8+ thymocytes. In secondary lymphoid organs, HA-reactive T cells were initially activated but were hyporesponsive at the single cell level. After 3 days, however, those cells were rapidly deleted, at least partially, through an apoptotic process. Therefore, both thymic and peripheral apoptosis, in addition to T-cell receptor desensitization, contribute to high-dose tolerance.T-cell tolerance to self antigens is acquired through both thymic and peripheral events. In the thymus, developing T cells are clonally deleted or, in some instances, anergized upon encountering their specific major histocompatibility complex (MHC)-self peptide ligands (1, 2). Nevertheless, some autoreactive T cells do enter the periphery and several mechanisms normally operate to prevent these autoreactive T cells from initiating an autoimmune disease. These mechanisms have been studied extensively in recent years, particularly in systems using mice transgenic for neo-self antigens expressed in a tissue-specific manner and/or using mice transgenic for the T-cell receptor (TCR). By using this technology, evidence for peripheral self tolerance through anergy (3), modulation of TCR and coreceptor molecule expression (2), clonal deletion (2), and clonal diversion (4) MATERIALS AND METHODSMice. The HNT-TCR transgenic mice were generated as described (4). For this study, one line, in which '50 copies of the TCR a transgene and 40 copies of the TCR 3 transgene had integrated in the same chromosomal location, was backcrossed at least five times on the B10.D2 (H-2d)

Steady‐state antigen‐expressing dendritic cells terminate CD4+ memory T‐cell responses

“…Thus, different mechanisms of tolerance may be prominent depending on the nature of the active tolerogenic APC population. Intravenous administration of peptide has been reported to result in a large-scale deletion of antigen-specific CD4 1 and CD8 1 naïve T cells [30,31] and also memory CD8 1 T cells [32] reminiscent of our findings here, however, induction of unresponsiveness also appears to provide some contribution to the tolerogenic effect. Traditionally, i.v.…”

“…Traditionally, i.v. peptide administration has been considered to constitute ''high-dose'' tolerance [30]. In various experimental systems, high antigen loads favor induction of unresponsiveness in CD8 1 T cells, both naïve and memory, whereas lower antigen loads favor deletion or induction of regulation [33,34], and our unpublished findings.…”

Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

“…If the liver is not a graveyard for activated cells, this raises the question of where the immune system eventually removes the large number of specific cells that arise during an immune response. The ultimate fate of activated CD8 ϩ T cells may resemble that of CD4 ϩ T cells, which undergo Ag-induced cell death in the peripheral organs where they are activated (65)(66)(67)(68).…”

Immune Modulation and Prevention of Autoimmune Disease by Repeated Sequences from Parasites Linked to Self Antigens

“…Different methods, such as the application of high or low doses of a specific antigen and defined routes of administration are critical factors that determine the induction of immune tolerance. The doses and concentration of the antigen are often directly correlated with the generation of active and cell-dependent regulatory mechanisms (Turley and Miller, 2010) or with the induction of anergy (Bitar and Whitacre, 1988) or even deletion of antigen-specific T cells (Critchfield et al, 1994;Liblau et al, 1996;Apostolou and von Boehmer, 2004;Judkowski et al, 2004). Likewise, immunological tolerance achieved by oral (Higgins and Weiner, 1988;Weiner, 2000;Weiner et al, 2011) and intranasal (Anderton et al, 1998;Fossati-Jimack et al, 2015) delivery of autoantigens has shown to be mediated by active suppressor mechanisms such as anti-inflammatory cytokines and regulatory cells (Chen et al, 1995;Weiner et al, 2011).…”