Type 1 regulatory T cells specific for collagen type II as an efficient cell-based therapy in arthritis

Abstract

IntroductionRegulatory T (Treg) cells play a crucial role in preventing autoimmune diseases and are an ideal target for the development of therapies designed to suppress inflammation in an antigen-specific manner. Type 1 regulatory T (Tr1) cells are defined by their capacity to produce high levels of interleukin 10 (IL-10), which contributes to their ability to suppress pathological immune responses in several settings. The aim of this study was to evaluate the therapeutic potential of collagen type II–specific Tr1 (Col-Treg) cells in two models of rheumatoid arthritis (RA) in mice.MethodsCol-Treg clones were isolated and expanded from collagen-specific TCR transgenic mice. Their cytokine secretion profile and phenotype characterization were studied. The therapeutic potential of Col-Treg cells was evaluated after adoptive transfer in collagen-antibody– and collagen-induced arthritis models. The in vivo suppressive mechanism of Col-Treg clones on effector T-cell proliferation was also investigated.ResultsCol-Treg clones are characterized by their specific cytokine profile (IL-10highIL-4negIFN-γint) and mediate contact-independent immune suppression. They also share with natural Tregs high expression of GITR, CD39 and granzyme B. A single infusion of Col-Treg cells reduced the incidence and clinical symptoms of arthritis in both preventive and curative settings, with a significant impact on collagen type II antibodies. Importantly, injection of antigen-specific Tr1 cells decreased the proliferation of antigen-specific effector T cells in vivo significantly.ConclusionsOur results demonstrate the therapeutic potential of Col-Treg cells in two models of RA, providing evidence that Col-Treg could be an efficient cell-based therapy for RA patients whose disease is refractory to current treatments.

Nonclassical CD4+CD49b+ Regulatory T Cells as a Better Alternative to Conventional CD4+CD25+ T Cells To Dampen Arthritis Severity

“…Nevertheless, in vitro expansion of Col II-specific Tr1 cells isolated from RA patients was recently demonstrated (57). Preclinical proof-of-concept concerning the therapeutic potential of in vitro generated Col II-specific Tr1 cells has also been recently validated in two experimental models of arthritis (40). Altogether, these results support the therapeutic use of ex vivo expanded autologous Ag-specific Treg cells in RA.…”

Enhanced immunoregulation of mesenchymal stem cells by IL-10-producing type 1 regulatory T cells in collagen-induced arthritis

“…These cells include CD4+CD25+Foxp3+ regulatory T (Treg) and/or IL-10-producing type 1 regulatory T (Tr1) cells and have been shown to play an important role in T cell homeostasis and maintenance of immune responses, including the prevention of autoimmunity and inflammation19202122. In vitro and in vivo studies suggest that MSCs can generate Treg cells; indeed, the immunosuppressive effects of MSCs may depend on their effects on Treg generation or function23.…”

Introduction: ‘Why is there persistent disease despite aggressive therapy of rheumatoid arthritis?’

“…Emery [3] rightly advocates that with RA we are always far too late and too often miss induction of remission. Although it makes sense to act early, we now better understand the underlying mechanisms.…”