Location of CD4+ T Cell Priming Regulates the Differentiation of Th1 and Th17 Cells and Their Contribution to Arthritis

Abstract

T helper (Th) cytokines IFN-γ and IL-17 are linked to the development of autoimmune disease. In models of rheumatoid arthritis (RA) i.e. proteoglycan (PG) -induced arthritis (PGIA), IFN-γ is required whereas in collagen-induced arthritis, IL-17 is necessary for development of arthritis. Here we show that the route of immunization determines the requirement for either IFN-γ or IL-17 in arthritis. Intraperitoneal (i.p.) immunization with PG induces a CD4+ T cell IFN-γ response with little IL-17 in the spleen and peripheral lymph nodes. However, s.c. immunization induces both an IFN-γ and an IL-17 CD4+ T cell response in spleen and LNs. The failure to induce a CD4+ T cell IL-17 response after i.p. immunization is associated with T cell priming as naïve T cells activated in vitro were fully capable of producing IL-17. Moreover, PGIA is converted from an IFN-γ to an IL-17-mediated disease by altering the route of immunization from i.p. to s.c. The histological appearance of joint inflammation (cellular inflammation and bone erosion) are similar in the i.p. versus s.c. immunized mice despite the presence of CD4+ T cells producing IL-17 in joint tissues only after s.c. immunization. These data indicate a critical role for the site of initial T cell priming and the Th cytokines required for susceptibility to arthritis. Our findings suggest that T cell activation at different anatomical sites in RA patients may skew the T cells towards production of either IFN-γ or IL-17.

N-Acetylcysteine protects against trichloroethene-mediated autoimmunity by attenuating oxidative stress

“…IL-17 is a potent pro-inflammatory cytokine produced by activated T cells, particularly Th17 cells, and has been associated with pathogenesis of a wide range of inflammatory and autoimmune diseases including SLE and RA (Miossec and Kolls, 2012; Nalbandian et al, 2009; Rodeghero et al, 2013). To investigate the impact of NAC supplementation on TCE-mediated IL-17 release, splenocytes isolated from control, TCE alone, NAC alone or TCE + NAC-treated mice were cultured with or without ConA or anti-mouse CD3/CD28, and the release of IL-17 into the culture supernatants was determined.…”

Rheumatoid arthritis vaccine therapies: perspectives and lessons from therapeutic ligand epitope antigen presentation system vaccines for models of rheumatoid arthritis

“…Although disease severity (arthritic index and histopathology), the presence of spondylitis, and even serum factors such as RF and anti-PG antibodies are similar, the dominant cytokines indicative of a Th1 or Th17 response differ depending on the route of immunization (intraperitoneal vs intradermal) used for arthritis induction [63]. The potential for Th1 or Th17 signature phenotypes in the same animal model has also been noted for animal models of MS [64] and uveitis [65].…”

Ginsenoside Metabolite Compound K Suppresses T-Cell Priming via Modulation of Dendritic Cell Trafficking and Costimulatory Signals, Resulting in Alleviation of Collagen-Induced Arthritis

“…RA has been regarded as a classic T cell-mediated chronic inflammatory autoimmune disease for years. Abnormal activation of T cells in RA are the main induced factors causing immune damage and synovial pathologic histology change (Alzabin and Williams, 2011;Rodeghero et al, 2013). In our previous study, we found that CK alleviated CIA and adjuvant-induced arthritis, downregulated the percentage of activated T cells, and upregulated naive T cells and regulatory T cells (Tregs) in spleen Liu et al, 2014).…”

“…The excessive activation of T cells causes undesirable immune responses against self-antigens, which then results in chronic inflammatory and autoimmune response (Pablos and Cañete, 2013;Rodeghero et al, 2013). In our previous study, a decreased percentage of naive T cells, a raised percentage of activated T cells, and hyperplasia of T cells were observed in autoimmune arthritis animal models (Chang et al, 2011;Liu et al, 2011;Song et al, 2013;Zhang et al, 2013).…”