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.
10.5051/jpis.2017.47.5.292
- Author:
Hyun Joo KIM
1
;
Gil Sun CHA
;
Ji Young JOO
;
Juyoun LEE
;
Sung Jo KIM
;
Jeongae LEE
;
So Youn PARK
;
Jeomil CHOI
Author Information
1. Department of Periodontology, Dental Research Institute, Pusan National University Dental Hospital, Pusan National University School of Dentistry, Yangsan, Korea. jrapa@pusan.ac.kr
- Publication Type:Original Article
- Keywords:
Adoptive transfer;
Autoimmune diseases;
Heat-shock proteins;
Immune tolerance;
Regulatory T-lymphocytes;
Rheumatoid arthritis
- MeSH:
Adoptive Transfer;
Animals;
Apoptosis;
Arthritis, Experimental;
Arthritis, Rheumatoid;
Autoimmune Diseases;
Dendritic Cells;
Epigenomics;
Eragrostis;
Heat-Shock Proteins;
Humans*;
Immune Tolerance;
Immunotherapy*;
In Vitro Techniques;
Interleukin-2;
Joints;
Mice;
Sensitivity and Specificity;
Sirolimus;
T-Lymphocytes;
T-Lymphocytes, Regulatory*;
Vaccination
- From:Journal of Periodontal & Implant Science
2017;47(5):292-311
- CountryRepublic of Korea
- Language:English
-
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.
