Down-regulation of myasthenogenic T cell responses by a dual altered peptide ligand via CD4⁺CD25⁺-regulated events leading to apoptosis

Abstract

The myasthenogenic peptides p195–212 and p259–271 are sequences of the human acetylcholine receptor and were shown to induce myasthenia gravis-associated immune responses in mice. A dual altered peptide ligand (APL) composed of the two APLs of the myasthenogenic peptides inhibited, in vitro and in vivo , those responses. The aims of this study were to elucidate the events that follow the in vivo treatment with the dual APL and to characterize the cell population that is induced by the latter. We demonstrate here that s.c. administration of the dual APL up-regulates CD4 + CD25 + regulatory T cells that are characterized by up-regulated expression of cytotoxic T lymphocyte-associated antigen 4, intracellular and membranal TGF-β, and Foxp3. Administration of the dual APL to mice concomitant with the immunization with either of the myasthenogenic peptides resulted also in the up-regulation of c-Jun-NH 2 -terminal kinase activity and of Fas signaling pathway molecules as determined by measuring Fas, Fas ligand, and caspase 8. Thus, our results suggest that the suppression of myasthenia gravis-associated T cell responses exerted by the dual APL is mediated by the CD4 + CD25 + immunoregulatory T cell function via TGF-β or cytotoxic T lymphocyte-associated antigen 4, which further stimulate a cascade of events that up-regulates apoptosis.

Altered keratin 17 peptide ligands inhibit in vitro proliferation of keratinocytes and T cells isolated from patients with psoriasis

“…IL-10 and IL-4 can actually reverse the T H 1 polarization of T cells, shifting from a IFN-g-producing (T H 1) to a IL-4-producing pattern, with evidence of clinical responses. 37 The up-regulation of TGF-b by altered peptide ligands 119R and 355L provided an additional hint about the functional activity of CD4 1 , CD25 1 regulatory T cells that are characterized by upregulated expression of cytotoxic T lymphocytee associated antigen, 4 intracellular and membrane TGF-b, and Foxp3-like other altered peptide ligands, 38 which needs further study. T-cell culture supernatants (1:100) from concentrations (10 and 100 g Á mL ÿ1 with 119R, 100 g Á mL ÿ1 with 355L) were more effective than ratios (1:10 and 1:1000) in inhibiting keratinocyte proliferation.…”

On Peptides and Altered Peptide Ligands: From Origin, Mode of Action and Design to Clinical Application (Immunotherapy)

“…In addition, the same group of authors have shown that the dual APLs also induce CD4+CD25+ [56] as well as CD8+CD28- [57] T cells. The CD4+CD25+ T cells, which upregulate a 50-kDa ERK-like protein upon dual APL stimulation [58], seem to maximize their regulatory function by coexpressing CTLA-4 and - along with the secretion of TGF-β - induce apoptosis of effector T cells [59]. …”

A Dual Altered Peptide Ligand Inhibits Myasthenia Gravis Associated Responses by Inducing Phosphorylated Extracellular‐regulated Kinase 1,2 that Upregulates CD4+CD25+Foxp3+ Cells

“…As ERK signalling is usually linked to proliferation and differentiation, the upregulation of dpERK1,2 in T‐cells of immunized and dual APL‐treated mice, has not been expected based on the well‐documented inhibitory effects of the dual APL [5–7, 10]. Therefore, we attempted the identification of the population of T‐cells that might use dpERK1,2 in the inhibition of MG associated responses that are mediated by the dual APL.…”

“…Furthermore, CD4 + CD25 + regulatory cells that are known to play a critical role in the maintenance of peripheral tolerance were found to be functionally involved in the suppressive action of the dual APL [8, 9]. Administration of the dual APL increased CD4 + CD25 + cells with regulatory characteristic markers [10, 11]. Depletion of CD4 + CD25 + cells diminished significantly the inhibitory effect observed after treatment with the dual APL [10].…”

“…Administration of the dual APL increased CD4 + CD25 + cells with regulatory characteristic markers [10, 11]. Depletion of CD4 + CD25 + cells diminished significantly the inhibitory effect observed after treatment with the dual APL [10].…”