Targeting the epitope spreader Pep19 by naïve human CD45RA⁺ regulatory T cells dictates a distinct suppressive T cell fate in a novel form of immunotherapy
Journal of Periodontal & Implant Science
;
: 292-311, 2017.
Artigo
em Inglês
| WPRIM
| ID: wpr-187090
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⁺CD127(lo−) Tregs (127-Tregs) and naïve 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 naïve CD4⁺CD25⁺CD45RA⁺ Tregs and the epitope spreader Pep19 as cellular and molecular targets for a novel antigen-specific Treg-based vaccination against collagen-induced arthritis.
Texto completo:
DisponíveL
Índice:
WPRIM (Pacífico Ocidental)
Assunto principal:
Artrite Experimental
/
Artrite Reumatoide
/
Doenças Autoimunes
/
Técnicas In Vitro
/
Células Dendríticas
/
Linfócitos T
/
Sensibilidade e Especificidade
/
Interleucina-2
/
Vacinação
/
Apoptose
Tipo de estudo:
Estudo diagnóstico
/
Estudo prognóstico
Limite:
Animais
/
Humanos
Idioma:
Inglês
Revista:
Journal of Periodontal & Implant Science
Ano de publicação:
2017
Tipo de documento:
Artigo
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