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.
Highlights
Regulatory 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
Transgenic mice carrying the rearranged Vα11.1 and Vβ 8.2 T-cell receptor (TCR) chain genes isolated from a collagen type Collagen type II (II) (Col II)–specific T-cell hybridoma were kindly provided by REM Toes (Leiden University Medical Center, Leiden, the Netherlands) with approval from W Ladiges [29]
Clones were selected based on Col II–specific TCR Vβ8 and CD4 expression (Figure 1A) as well as on their cytokine secretion profile: IL-10highIL-4negIFN-γint (Figure 1B and C)
Summary
Regulatory 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. Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and destruction of joint cartilage and bone and mediated by persistent synthesis of proinflammatory cytokines and matrix metalloproteinases. Proinflammatory cytokines such as interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) and IL-1β are critical mediators in the inflammatory process of arthritis [1,2]. Treatment of RA patients with anti-TNF antibodies has been shown to induce differentiation of a potent population of Treg cells with suppressive activity that is dependent upon transforming growth factor β (TGF-β) and IL-10 [12,13]
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