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KMID : 1044820170470050292
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Journal of Periodontal & Implant Science
2017 Volume.47 No. 5 p.292 ~ p.311
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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
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Kim Hyun-Joo
Cha Gil-Sun
Joo Ji-Young
Lee Ju-Youn
Kim Sung-Jo
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Abstract
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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 naive CD4+CD25+CD45RA+ Tregs (45RA-Tregs) were isolated and were stimulated with target peptide 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 CD95L-mediated 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 naive CD4+CD25+CD45RA+ Tregs and the epitope spreader Pep19 as cellular and olecular targets for a novel antigen-specific Treg-based vaccination against collagen-induced arthritis.
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KEYWORD
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Adoptive transfer, Autoimmune diseases, Heat-shock proteins, Immune tolerance, Regulatory T-lymphocytes, Rheumatoid arthritis
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