Functional defect of regulatory CD4+CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis

Abstract

Thymus-derived CD4 IntroductionThe development of autoimmune diseases involves a breakdown in the mechanisms that control self-reactive lymphocytes. The primary mechanism that generally maintains self-tolerance is thymic deletion of autoreactive T cells with high affinity for self-antigens. However, this mechanism is not perfect and autoreactive T cells do escape to the periphery. Recent data suggest that in addition to the mechanisms of clonal deletion and anergy, regulatory T (Treg) cells play a significant role in the generation and maintenance of peripheral tolerance. Indeed, compelling evidence indicates that immune responsiveness is controlled by a subpopulation of Treg cells that are enriched in the naturally activated subset of CD4 T cells and that constitutively express the CD25 (interleukin 2 receptor ␣ [IL-2R␣]) molecule. The thymus is a primary source of this regulatory CD4 ϩ CD25 ϩ T-cell subset, which participates in the active suppression of potentially autoreactive T cells in the periphery. 1,2 CD4 ϩ CD25 ϩ Treg cells have been described in a variety of experimental systems to provide protection from T cell-mediated autoimmune disorders (for a review, see Shevach 3 ). This Treg population has been also isolated from human thymus 4,5 and the peripheral blood of healthy individuals. [6][7][8] Similar to murine CD25 ϩ T cells, 9 they are naturally anergic in vitro and they inhibit the proliferation of cocultured conventional CD4 ϩ CD25 Ϫ T cells in a contact-dependent manner. The possible role of the surface molecules, cytotoxic T lymphocyte associated-antigen 4 (CTLA-4) and transforming growth factor ␤ (TGF-␤), in the regulatory function of CD25 ϩ Treg cells is controversial and their mechanisms of suppression remain to be determined. 3 The forkhead transcription factor, FoxP3, was reported recently to be essential for the development and functional activity of mice and human CD25 ϩ Treg cells. [10][11][12][13] Moreover, FOXP3 transduction converts naïve CD4 ϩ CD25 Ϫ T cells into CD25 ϩ regulatory cells with suppressive activity. Despite a growing interest in CD4 ϩ CD25 ϩ Treg cells and their role in the emergence of autoimmune diseases in animal models, only very limited and controversial information is available on the role of this T-cell population in the pathogenesis of human autoimmune diseases. Indeed, a decrease in the number of circulating CD4 ϩ CD25 ϩ cells in autoimmune diabetes was reported. 14 In multiple sclerosis, either an increase 15 or no alteration 16 was shown, although a very recent paper showed the loss of functional activity for circulating CD4 ϩ CD25 ϩ T cells. 17 In contrast, the CD4 ϩ CD25 ϩ T-cell subset was enriched with functionally active regulatory cells in the inflamed joints of patients with rheumatoid arthritis. 18 The deficiency in numbers of CD4 ϩ CD25 ϩ T cells was reported in the peripheral blood leukocytes (PBLs) of patients with virus-associated autoimmunity hepatitis C-mixed cryoglobulinemia vasculitis, whereas suppressive activity of Treg cells was not chang...

Diabetes in non‐obese diabetic mice is not associated with quantitative changes in CD4+ CD25+ Foxp3+ regulatory T cells

“…Ó 2007 Blackwell Publishing Ltd, Immunology, 121, [15][16][17][18][19][20][21][22][23][24][25][26][27][28] that over-expressed Foxp3 had increased numbers of Tregs in the periphery. [8][9][10] Dysregulation of Treg function has been implicated as an important event in the development of autoimmunity in animal models and in spontaneous autoimmune diseases in humans.…”

“…[17][18][19] Defects in Treg function have also been observed in other autoimmune diseases, including rheumatoid arthritis, myasthenia gravis, multiple sclerosis and autoimmune polyglandular syndrome type II. [20][21][22][23] In addition, reversal of compromised Treg function has been demonstrated in humans with rheumatoid arthritis who experienced clinical improvement following anti-tumour necrosis factor-a therapy. 20 In light of these observations, we evaluated the frequency and function of Tregs in our NOD mouse colony.…”

Peripheral blood regulatory T cells in patients with diffuse systemic sclerosis (SSc) before and after autologous hematopoietic SCT: a pilot study

“…2,7 The various Treg cells have key roles in maintaining self-tolerance and modulating the allergic and autoimmune responses, while controlling autoreactive T cells. [8][9][10][11] Several studies have reported a deficiency in the number of Treg and/or function in autoimmune disease patients, 12,13 namely in systemic lupus erythematous, 14 rheumatoid arthritis, 15 multiple sclerosis, 16 autoimmune polyglandular syndrome II, 17 myasthenia gravis 18 and type I diabetes. 19 However, results concerning the number of circulating Treg cells and their suppressive function have been contradictory.…”

Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression

“…The development and function of T R cells is controlled by Foxp3 (refs 1, 2), a lack of which results in loss of T R cells and massive multi-organ autoimmunity in scurfy mice and IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients 3,4 . It is generally thought that, through a binary mechanism, Foxp3 expression serves as an on-and-off switch to regulate positively the physiology of T R cells; however, emerging evidence associates decreased Foxp3 expression in T R cells with various immune disorders [5][6][7] . We hypothesized that Foxp3 regulates T R cell development and function in a dose-dependent, nonbinary manner, and that decreased Foxp3 expression can cause immune disease.…”