Targeting the epitope spreader Pep19 by naive human CD45RA+ regulatory T cells dictates a distinct suppressive T cell fate in a novel form of immunotherapy

Title
Targeting the epitope spreader Pep19 by naive human CD45RA+ regulatory T cells dictates a distinct suppressive T cell fate in a novel form of immunotherapy
Authors
이정애김현주차길선주지영이주연김성조박수연최점일
Keywords
Adoptive transfer; Autoimmune diseases; Heat-shock proteins; Immune tolerance; Regulatory T-lymphocytes; Rheumatoid arthritis
Issue Date
2017-10
Publisher
Journal of Periodontal and Implant Science
Citation
VOL 47, NO 5-311
Abstract
Purpose: Beyond the limited scope of non-specific polyclonal regulatory T cell (Treg)-based immunotherapy, which depends largely on serendipity, the present study explored a target Treg subset appropriate for the delivery of a novel epitope spreader Pep19 antigen as part of a sophisticated form of immunotherapy with defined antigen specificity that induces immune tolerance. Methods: Human polyclonal CD4+CD25+CD127lo− Tregs (127-Tregs) and naï ve CD4+CD25+ CD45RA+ Tregs (45RA-Tregs) were isolated and were stimulated with targetpeptide 19 (Pep19)-pulsed dendritic cells in a tolerogenic milieu followed by ex vivo expansion. Low-dose interleukin-2 (IL-2) and rapamycin were added to selectively exclude the outgrowth of contaminating effector T cells (Teffs). The following parameters were investigated in the expanded antigen-specific Tregs: the distinct expression of the immunosuppressive Treg marker Foxp3, epigenetic stability (demethylation in the Treg-specific demethylated region), the suppression of Teffs, expression of the homing receptors CD62L/CCR7, and CD95Lmediated apoptosis. The expanded Tregs were adoptively transferred into an NOD/scid/IL-2Rγ− /− mouse model of collagen-induced arthritis. Results: Epitope-spreader Pep19 targeting by 45RA-Tregs led to an outstanding in vitro suppressive T cell fate characterized by robust ex vivo expansion, the salient expression of Foxp3, high epigenetic stability, enhanced T cell suppression, modest expression of CD62L/CCR7, and higher resistance to CD95L-mediated apoptosis. After adoptive transfer, the distinct fate of these T cells demonstrated a potent in vivo immunotherapeutic capability, as indicated by the complete elimination of footpad swelling, prolonged survival, minimal histopathological changes, and preferential localization of CD4+CD25+ Tregs at the articular joints in a mechanistic and orchestrated way. Conclusions: We propose human n
URI
http://pubs.kist.re.kr/handle/201004/66400
ISSN
2093-2278
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KIST Publication > Article
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