Resistance to regulatory T cell-mediated suppression in rheumatoid arthritis can be bypassed by ectopic foxp3 expression in pathogenic synovial T cells

Abstract

Increasing evidence suggests that regulatory T cell (Treg) function is impaired in chronic inflammatory diseases such as rheumatoid arthritis (RA). Here we demonstrate that Tregs are unable to modulate the spontaneous production of TNF-α from RA synovial cells cultured from the diseased synovium site. Cytokine (IL-2, IL-6, TNF-α) activated T cells (Tck), cells we previously demonstrated to mimic the effector function of pathogenic RA synovial T cells, contained Tregs that survived and divided in this cytokine environment; however, the up-regulation of key molecules associated with Treg function (CTLA-4 and LFA-1) was impaired. Furthermore, Tregs were unable to suppress the function of Tcks, including contact-dependent induction of TNF-α from macrophages, supporting the concept that impaired Treg function/responsiveness contributes to chronicity of RA. However, ectopic foxp3 expression in both Tcks and pathogenic RA synovial T cells attenuated their cytokine production and function, including contact-dependent activation of macrophages. This diminished response to cytokine activation after ectopic foxp3 expression involved inhibited NF-κB activity and differed mechanistically from that displayed endogenously in conventional Tregs. These results suggest that diseases such as RA may perpetuate owing to the inability of Tregs to control cytokine-activated T-cell function. Understanding the mechanism whereby foxp3 attenuates the pathogenic function of synovial T cells may provide insight into the mechanisms of chronicity in inflammatory disease and potentially reveal new therapeutic candidates.

Exclusive Transduction of Human CD4+ T Cells upon Systemic Delivery of CD4-Targeted Lentiviral Vectors

“…Our data are consistent with previous studies demonstrating that CAR-engineered CD4 + T cells are capable of direct cytotoxicity and can drive specific cytolysis of target tumor cells (47)(48)(49). Beyond cancer, consistent gene transfer of FOXP3 into CD4 + cells is potent in inducing functional Tregs, which may be of relevance for novel therapeutic strategies in autoimmune and inflammatory diseases (3,4,50). In line with this idea, we demonstrated the feasibility of achieving continuous ectopic FOXP3 expression in CD4 + cells upon in vivo gene delivery by CD4-LV.…”

“…Moreover, recent studies have demonstrated that functional human regulatory T cells (Tregs) can be efficiently and consistently induced by ectopic FOXP3 expression mediated by lentiviral gene transfer in genetic autoimmune disease (3) and rheumatoid arthritis (4). Hence, CD4 + T cells are important target cells not only for understanding fundamental immunology but also for gene therapy and immunotherapy approaches.…”

“…In this study, the human FOXP3 gene, previously demonstrated to be potent in generating suppressive inducible Tregs (4,30), was transferred by CD4-LV. In T cell lines, CD4-LV mediated efficient expression of FOXP3 as compared with ut A301 cells (Fig.…”

Polyfunctional, Pathogenic CD161+ Th17 Lineage Cells Are Resistant to Regulatory T Cell–Mediated Suppression in the Context of Autoimmunity

“…Suppression assays performed by two independent groups illustrated that Tregs from the SF of RA patients suppressed effector cell proliferation and reduced the concentrations of TNF and IFN-g produced in the supernatants (4,5), suggesting that Tregs in the synovial joint are in fact suppressive yet fail to constrain inflammation. On the other hand, Tregs from the peripheral blood of RA patients have been shown to be functionally impaired (6)(7)(8)(9).…”

Rheumatoid Arthritis: Prospects for Stopping the Runaway Train by Reintroduction of Tolerance

“…Rather, their Tregs appear to be dysfunctional, with a loss of ability to suppress inflammatory cytokines such as TNF-α and interferon γ [81,82]. TNF-α, which is present in abundance in the rheumatoid joint, seems to be the major mediator of this down regulation [82][83][84][85]. This may occur through TNF-α inducing the release of PKCθ which blocks CTLA-4 binding [82].…”