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Persistence of peptide-induced CD4+ T cell anergy in vitro.

Ryan KR, Evavold BD - J. Exp. Med. (1998)

Bottom Line: The anergic state was characterized by blunted proliferation and interleukin (IL) 2 production upon restimulation with Hb(64-76), and was not the result of impaired TCR/CD3 downmodulation.Interestingly, persistence of the anergic phenotype was observed despite biweekly restimulation with antigen, APCs, and IL-2.Thus, T cell unresponsiveness induced by a peptide produced a stable, persistent anergic state in a Th0 clone that was not reversible by stimulation with IL-2 or -12.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Emory University, Atlanta, Georgia 30322, USA.

ABSTRACT
Clonal T cell unresponsiveness, or anergy, has been proposed as a mechanism of peripheral tolerance in vivo, and as a potential means of curbing unwanted T cell responses. In this study, anergy was induced in a T helper cell (Th) clone reactive to hemoglobin (Hb) peptide 64-76 by coculture of the T cells with live antigen-presenting cells (APCs) and 74L, a peptide analog of Hb(64-76) that contains a single amino acid substitution of leucine for glycine at position 74, or with a low concentration of the agonist ligand. The anergic state was characterized by blunted proliferation and interleukin (IL) 2 production upon restimulation with Hb(64-76), and was not the result of impaired TCR/CD3 downmodulation. The addition of exogenous IL-12 transiently restored proliferation of the anergic lines, but removal of IL-12 from culture returned the T cells to their nonproliferative state. Interestingly, persistence of the anergic phenotype was observed despite biweekly restimulation with antigen, APCs, and IL-2. Thus, T cell unresponsiveness induced by a peptide produced a stable, persistent anergic state in a Th0 clone that was not reversible by stimulation with IL-2 or -12.

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Clone I is anergized by 0.1 μM Hb(64–76) and live APCs.  Clone I was cultured with 0.1 μm Hb(64–76) and live DCEK cells, then  restimulated 1 wk later with APCs and concentrations of Hb(64–76). Proliferation was measured by DNA incorporation of [3H]thymidine.
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Figure 3: Clone I is anergized by 0.1 μM Hb(64–76) and live APCs. Clone I was cultured with 0.1 μm Hb(64–76) and live DCEK cells, then restimulated 1 wk later with APCs and concentrations of Hb(64–76). Proliferation was measured by DNA incorporation of [3H]thymidine.

Mentions: Since partial agonist peptides stimulate minimal proliferation and induce clonal unresponsiveness (10, 17), we examined whether a submitogenic concentration of wild-type (wt)1 peptide might also induce anergy. A comparison of the proliferation dose–response curves of clone I reveals that the level of proliferation produced by 0.1 μM Hb(64–76) is comparable to the proliferation seen with 10 μM 74L (Fig. 1). T cells were placed in culture with 0.1 μM Hb(64–76) and live APCs, and were tested 1 wk later for their ability to proliferate to Hb(64– 76). As shown in Fig. 3, the T cells exposed to 0.1 μM Hb(64–76) were anergic.


Persistence of peptide-induced CD4+ T cell anergy in vitro.

Ryan KR, Evavold BD - J. Exp. Med. (1998)

Clone I is anergized by 0.1 μM Hb(64–76) and live APCs.  Clone I was cultured with 0.1 μm Hb(64–76) and live DCEK cells, then  restimulated 1 wk later with APCs and concentrations of Hb(64–76). Proliferation was measured by DNA incorporation of [3H]thymidine.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199180&req=5

Figure 3: Clone I is anergized by 0.1 μM Hb(64–76) and live APCs. Clone I was cultured with 0.1 μm Hb(64–76) and live DCEK cells, then restimulated 1 wk later with APCs and concentrations of Hb(64–76). Proliferation was measured by DNA incorporation of [3H]thymidine.
Mentions: Since partial agonist peptides stimulate minimal proliferation and induce clonal unresponsiveness (10, 17), we examined whether a submitogenic concentration of wild-type (wt)1 peptide might also induce anergy. A comparison of the proliferation dose–response curves of clone I reveals that the level of proliferation produced by 0.1 μM Hb(64–76) is comparable to the proliferation seen with 10 μM 74L (Fig. 1). T cells were placed in culture with 0.1 μM Hb(64–76) and live APCs, and were tested 1 wk later for their ability to proliferate to Hb(64– 76). As shown in Fig. 3, the T cells exposed to 0.1 μM Hb(64–76) were anergic.

Bottom Line: The anergic state was characterized by blunted proliferation and interleukin (IL) 2 production upon restimulation with Hb(64-76), and was not the result of impaired TCR/CD3 downmodulation.Interestingly, persistence of the anergic phenotype was observed despite biweekly restimulation with antigen, APCs, and IL-2.Thus, T cell unresponsiveness induced by a peptide produced a stable, persistent anergic state in a Th0 clone that was not reversible by stimulation with IL-2 or -12.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Emory University, Atlanta, Georgia 30322, USA.

ABSTRACT
Clonal T cell unresponsiveness, or anergy, has been proposed as a mechanism of peripheral tolerance in vivo, and as a potential means of curbing unwanted T cell responses. In this study, anergy was induced in a T helper cell (Th) clone reactive to hemoglobin (Hb) peptide 64-76 by coculture of the T cells with live antigen-presenting cells (APCs) and 74L, a peptide analog of Hb(64-76) that contains a single amino acid substitution of leucine for glycine at position 74, or with a low concentration of the agonist ligand. The anergic state was characterized by blunted proliferation and interleukin (IL) 2 production upon restimulation with Hb(64-76), and was not the result of impaired TCR/CD3 downmodulation. The addition of exogenous IL-12 transiently restored proliferation of the anergic lines, but removal of IL-12 from culture returned the T cells to their nonproliferative state. Interestingly, persistence of the anergic phenotype was observed despite biweekly restimulation with antigen, APCs, and IL-2. Thus, T cell unresponsiveness induced by a peptide produced a stable, persistent anergic state in a Th0 clone that was not reversible by stimulation with IL-2 or -12.

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