CD4+CD25bright Regulatory T Cells Actively Regulate Inflammation in the Joints of Patients with the Remitting Form of Juvenile Idiopathic Arthritis

Abstract

This study investigates the role of CD4+CD25+ regulatory T cells during the clinical course of juvenile idiopathic arthritis (JIA). Persistent oligoarticular JIA (pers-OA JIA) is a subtype of JIA with a relatively benign, self-remitting course while extended oligoarticular JIA (ext-OA JIA) is a subtype with a much less favorable prognosis. Our data show that patients with pers-OA JIA display a significantly higher frequency of CD4+CD25bright T cells with concomitant higher levels of mRNA FoxP3 in the peripheral blood than ext-OA JIA patients. Furthermore, while numbers of synovial fluid (SF) CD4+CD25bright T cells were equal in both patient groups, pers-OA JIA patients displayed a higher frequency of CD4+CD25int T cells and therefore of CD4+CD25total in the SF than ext-OA JIA patients. Analysis of FoxP3 mRNA levels revealed a high expression in SF CD4+CD25bright T cells of both patient groups and also significant expression of FoxP3 mRNA in the CD4+CD25int T cell population. The CD4+CD25bright cells of both patient groups and the CD4+CD25int cells of pers-OA JIA patients were able to suppress responses of CD25neg cells in vitro. A markedly higher expression of CTLA-4, glucocorticoid-induced TNFR, and HLA-DR on SF CD4+CD25bright T regulatory (Treg) cells compared with their peripheral counterparts suggests that the CD4+CD25+ Treg cells may undergo maturation in the joint. In correlation with this mature phenotype, the SF CD4+CD25bright T cells showed an increased regulatory capacity in vitro compared with peripheral blood CD4+CD25bright T cells. These data suggest that CD4+CD25bright Treg cells play a role in determining the patient’s fate toward either a favorable or unfavorable clinical course of disease.

Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte glycoprotein in patients with multiple sclerosis

“…A similar subpopulation of CD4 + CD25 high T cells is present in human peripheral blood and lymphoid organs [6][7][8][9][10][11][12][13]. From a few recent studies, it appears that T reg numbers are reduced or their function is impaired in patients with various autoimmune disorders [17][18][19][20][21][22][23][24]. The impact of CD4 + CD25 high T cells in immunoregulation is critically supported by observations of Bennett et al [37] who demonstrated that mutations of Foxp3, a transcription factor which is essential for CD4 + CD25 high T cell function, cause the immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX).…”

“…Implication of T reg in human autoimmune disease is currently under intense investigation. Either reduced numbers or suppressive capacities of T reg were recently reported in patients affected by type-1 diabetes [17,18], juvenile idiopathic arthritis [19], systemic lupus erythematosus [20], hepatitis C-associated mixed cryoclobulinemia vasculitis [21], autoimmune polyglandular syndrome type II [22], and psoriasis [23].…”

Interleukin-18 as a mediator of systemic juvenile idiopathic arthritis

“…Several aspects of immune dysregulation in JIA have been described, including alteration of regulatory T cell numbers, as well as abnormal chemokine and cytokine production, especially IL-1β, IL-6 and TNF-α [2][3][4][5]. Among the cytokines, IL-18 should also be particularly interesting with respect to the pathogenesis of JIA.…”

Global Natural Regulatory T Cell Depletion in Active Systemic Lupus Erythematosus

“…In the latter studies, the underlying defect accounting for the inability of the patient's Tregs to suppress lymphocyte proliferation and/or cytokine production could not be identified. Other authors reported that Tregs isolated from patients affected by various types of rheumatoid disorders (rheumatoid arthritis, spondyloarthropathies, and juvenile idiopathic arthritis) presented no apparent functional deficiency (32)(33)(34). Comparison between these studies is complicated by the fact that a means of defining phenotypically Tregs in humans is still lacking.…”