Glucocorticoid-mediated control of the activation and clonal deletion of peripheral T cells in vivo.

Abstract

SummaryPoly-and oligodonal T cell stimuli like anti-CD3e monoclonal antibody or Staphylococcus aureus enterotoxin B (SEB), injected at doses that per se are not lethal, provoke acute death within less than 24 h, provided that endogenous glucocorticoids (GC) are depleted by adrenalectomy or by injection of saturating amounts of the GC receptor antagonist RU-38486 (mifepristone). Pharmacological doses of the GC agonist dexamethasone (DEX) alter the in vivo response of splenic V38 + T cells to SEB, thus impeding the expansion of such cells and causing their rapid (3 d) clonal deletion. In contrast, coadministration of RU-38486 counteracts a SEB-induced early (12 h) reduction of V38+CD4 + and V38+CD8 + spleen cells. In vivo T cell stimulation by injection of bacterial superantigen induces a rapid (peak at 90-120 rain) increase in corticosterone serum levels, suggesting that endogenous GC might control early T cell activation. Accordingly, kinetic studies revealed that RU-38486 has to be administered within 2 h after superantigen administration to exert its lethal effect. Similarly, exogenous GC must be injected during this critical phase (2 h) to rescue animals from acute death induced by coinjection of SEB and D-galactosamine (GAIN). Adrenalectomy, injection of RU-38486 and priming with GaIN per se provoke the programmed death of peripheral CD4 + and CD8 + T cells. Thus, three manipulations that sensitize mice for the lethal effect of T cell stimulation also exert a proapoptotic effect on peripheral T cells. In synthesis, endogenous and exogenous GC regulate T cell responses and determine the propensity of peripheral T cells to undergo apoptosis. SYnthetic glucocorticoid (GC) 1 agonists are used for therapy of a broad spectrum of organ-specific and generalized autoimmune diseases. In the same way, endogenous GC secreted by the adrenal glands may act as immunosuppressive and antiinflammatory agents that contend lifethreatening overreactions of the immune system, as well as autoaggressive responses (for reviews see references 1, 2). GC inhibit macrophage functions, including cytotoxic functions, processing, and presentation of antigen to T cells, inhibit the production of IL-2 and IFN-3, in T lymphocytes (3), shift T cell responses from the Thl to the Th2 type (4), decrease the activity of NK cells, induce programmed cell death in a variety of different immunologically relevant cells, including immature T and B cell precursors (for reviews see references 5, 6) and mature T cells (7), and inhibit the synthesis of a variety of proimflammatory cytokines (IL-1, IL-6, and TNF-o 0 (8). Immune activation frequently is associated with an in- crease in ACTH and GC secretion, and the susceptibility of certain animal strains to develop autoimmune diseases is linked to a deficient GC-mediated inhibition of immune function (2, 9-12).Recently, a synthetic steroid, KU-38486 (RU486, mifepristone), with potent antiprogestational and antiglucocorticoid activity has become available for clinical use as an abortifacient agent (13,14) an...

Cytokine-induced IL-10–secreting CD8 T cells represent a phenotypically distinct suppressor T-cell lineage

“…Circulating levels of natural corticosterone are known to be elevated during episodes of acute inflammation, for example, during superantigen responses. 27,28 It can be envisaged that excessive T-cell-APC stimulation would …”

Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potential during apoptosis

“…One particularity of this in vivo system of apoptosis induction is that DEX-primed splenocytes fail to exhibit alterations associated with late apoptosis such as chromatinolysis and DNA fragmentation. This can be explained by the effective elimination of dying lymphocytes before endstage apoptosis is attained [23]. When compared to sham-treated controls, a relatively high percentage of DEX-primed splenocytes exhibits a low AHrn, as measured by means of the cationic lipophilic fluorochrome DiOCr(3) ( [3] and Fig.…”

“…injections of dexamethasone (DEX; 1 mg; Sigma, St. Louis, MO) or PBS as a vehicle control (200 p.1) [23]. Splenocytes were prepared on ice, depleted from erythrocytes by hypotonic lysis [24], and maintained in complete culture medium (RPMI 1640 medium supplemented with 10% FCS, L-glutamine, HEPES and antibiotics) at 0 to 4°C until labeling and analysis.…”

Immune Mediated Diseases and Immune Modulation in the Neurocritical Care Unit

“…Some of the nongenomic effects include inhibition of inflammatory cytokine secretion due to decreased stability of mRNA for genes of inflammatory proteins and impairment of leukocyte adhesion, extravasation, and entry into inflamed tissue [333]. Furthermore, corticosteroids cause T-cell apoptosis and lead to a transient rise in circulating neutrophils due to accelerated release from the bone marrow and reduced migration out of the blood into inflammatory sites [334,335].…”