Abstract
It is now generally accepted that CD4+CD25+ Treg cells play a major role in the prevention of autoimmunity and pathological immune responses. Their involvement in the pathogenesis of chronic arthritis is controversial, however, and so we examined their role in experimental antigen-induced arthritis in mice. Depletion of CD25-expressing cells in immunized animals before arthritis induction led to increased cellular and humoral immune responses to the inducing antigen (methylated bovine serum albumin; mBSA) and autoantigens, and to an exacerbation of arthritis, as indicated by clinical (knee joint swelling) and histological scores. Transfer of CD4+CD25+ cells into immunized mice at the time of induction of antigen-induced arthritis decreased the severity of disease but was not able to cure established arthritis. No significant changes in mBSA-specific immune responses were detected. In vivo migration studies showed a preferential accumulation of CD4+CD25+ cells in the inflamed joint as compared with CD4+CD25- cells. These data imply a significant role for CD4+CD25+ Treg cells in the control of chronic arthritis. However, transferred Treg cells appear to be unable to counteract established acute or chronic inflammation. This is of considerable importance for the timing of Treg cell transfer in potential therapeutic applications.
Highlights
Rheumatoid arthritis (RA) is the most common autoimmune disease in humans, affecting 1% of the population in western countries
Apart from adaptive Treg cells, which can be induced by antigen-specific stimulation of conventional peripheral T cells under tolerogenic conditions, there is no doubt that naturally occurring Treg cells exist in healthy mice as well as in humans and rats, and these are characterized by constitutive expression of CD25 [3,4,5]
Treg cells can be found in the CD25- compartment, based on the expression of the AIA = antigen-induced arthritis; CFSE = 5,6-carboxyfluorescein diacetate succinimidyl ester; DTH = delayed-type hypersensitivity; ELISA = enzymelinked immunosorbent assay; FACS = fluorescence-activated cell sorting; FCS = fetal calf serum; IFN = interferon; IL = interleukin; mBSA = methylated bovine serum albumin; PBS = phosphate-buffered saline; RA = rheumatoid arthritis; SCID = severe combined immunodeficient; Treg = regulatory T cell
Summary
Rheumatoid arthritis (RA) is the most common autoimmune disease in humans, affecting 1% of the population in western countries. Apart from adaptive Treg cells, which can be induced by antigen-specific stimulation of conventional peripheral T cells under tolerogenic conditions (for review [2]), there is no doubt that naturally occurring Treg cells exist in healthy mice as well as in humans and rats, and these are characterized by constitutive expression of CD25 [3,4,5]. Absence of these cells in vivo results in a multi-organ autoimmune syndrome [3,6].
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