Immunoregulation is an integral part of normal innate and adaptive immune responses. Recently, the literature has burgeoned with the reports of the regulatory properties of CD4+ T cells which constitutively express CD25. It is clear that regulation does not reside exclusively within this group but has also been attributed to subsets of CD8+ T cells (see above), dendritic cells, NK cells, neutrophils and eosinophils, as well as to the plethora of soluble regulatory molecules. A tangential but germane observation is that pathogenic microbes have developed an astonishing capacity for host immunointerference. Many multicellular parasites exemplify the delicate balance of immunomodulation without global immunosuppression; this permits chronic infection of the host, often over decades.
Dr L Taams (Kings College, London, UK) presented comparisons of the phenotype and function of CD4+CD25+ T cells in healthy controls and in both peripheral blood and SF of patients with RA. In vitro, the CD4+CD25+ T cells from RA and control peripheral blood were equally potent at inhibiting the proliferation of CD4+CD25- T cells. The CD4+CD25+ T cells derived from RA SF were more potent suppressors but, curiously, the CD4+CD25- T cells from SF were more resistant to proliferative suppression. Peripheral blood CD4+CD25+ cells modified cytokine release in an antigen-specific stimulation of CD4+CD25- cells. TNF-α production was reduced in CD4+CD25- cells from peripheral blood, whereas IFN-γ and IL-10 were both decreased in CD25- cells from SF. Continuing the theme of regulatory T cells in RA, Michael Ehrenstein (Centre for Rheumatology Research, London, UK) discussed the change in function of CD4+CD25+ T cells in the peripheral blood of patients with RA before and after TNF-α blocking therapy. In comparison with healthy controls, patients with RA demonstrated a defect in the ability of their CD4+CD25+ T cells to inhibit the production of TNF-α by monocytes. This defect was unchanged by treatment with methotrexate but was restored in patients who were successfully treated with TNF-α blockade.
Dr L Wedderburn (Institute of Child Health, London, UK) advanced the hypothesis that immune regulation contributes to the mild phenotype of children with oligoarticular juvenile idiopathic arthritis compared with patients with extended oligoarthritis. The CD25+ and particularly CD25hi T cells in the SF of patients with juvenile idiopathic arthritis exhibited a regulatory phenotype (GITR+, CTLA-4+, [FoxP3 mRNA]high). The regulatory activity of this subset was also supported by the demonstration that depletion of SF CD25+ cells releases the proliferation of CD25- cells. T cells in SF from children with oligoarthritis expressed an approximately ten-fold higher CD25 expression than T cells from patients with extended oligoarthritis, which is of particular interest because the most potent regulatory activity has been shown to reside in the CD4+CD25hi subset. Children with mild disease also had higher overall numbers of CD4+CD25+ cells in the SF. Although suppressive potency per cell seemed comparable in cells from patients with mild and severe disease, these observations are consistent with the hypothesis that the CD4+CD25+ regulatory subset is less effective in the children who develop extended oligoarticular arthritis.
Frances Hall (University of Cambridge School of Clinical Medicine, UK) presented data from a murine model of inflammatory arthritis that suggested a role for regulatory T cells in the repression of arthritis and dermatitis. Adult DBA/1 males were thymectomised and then treated with CD25-depleting antibody, which depleted both CD4+CD25med and CD4+CD25hi cells. Although a low level of inflammatory arthritis is usually evident in elderly DBA/1 males, the CD25-depleted mice developed more severe arthritis. Histologically, this was associated with pannus formation and erosions. In addition, about 60% of the CD25-depleted mice also developed an ulcerating rash, characterised by a dense neutrophilic infiltrate. The nature of the emerging inflammatory disease and the influence of the genetic background of the mice is currently under investigation.
Dr L Pazmany (Clinical Sciences Centre, Liverpool, UK) broadened the immunoregulatory discussion by considering the role of NK cells. NK cells are present at autoimmune sites of pathology, including the rheumatoid joint . In the murine model of extrinsic allergic encephalitis, depletion of NK cells resulted in an exacerbation of disease. For other models of autoimmune disease, results of NK depletion have been variable. The effect of addition of autologous NK cells to a PPD-pulsed culture of T cells and autologous antigen-presenting cells was investigated, using proliferation as a read-out. The effect of freshly isolated NK cells was dependent on the donor. However, NK cells incubated with IL-12 reproducibly inhibited T cell proliferation, even at NK:T ratios of 1:10. The significance of these observations for the susceptibility of individuals to RA and for the severity of disease is being investigated.
Professor I McInnes (University of Glasgow, UK) demonstrated how the immunoregulatory prowess of multicellular parasites might inform our search for the optimal disease-modifying agent. The filarial protein ES62 promotes a Th2 response in the BALB/c mouse. It seems to bind to TLR4 and promotes the development of type 2 dendritic cells, thereby decreasing IL-12 and TNF-α production by macrophages. In the murine collagen-induced arthritis model, serial subcutaneous ES62 administration decreases the severity, although not the incidence, of disease . This is associated with a decrease in the proliferation and production of IL-6, IFN-γ and TNF-α by draining lymph node cells from bovine collagen type II immunised mice. This effect of ES62 is mirrored by a decrease in the production of TNF-α and IL-6 in primary synovial membrane cultures. Because parasitic products such as ES62 might be well tolerated for decades, without global immunosuppression, they seem a promising therapeutic strategy for Th1-dominant inflammatory diseases, such as RA.