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...
IL-21 is a cytokine that regulates the activation of T and NK cells and promotes the proliferation of B cells activated via CD40. In this study, we show that rIL-21 strongly induces the production of all IgG isotypes by purified CD19+ human spleen or peripheral blood B cells stimulated with anti-CD40 mAb. Moreover, it was found to specifically induce the production of IgG1 and IgG3 by CD40-activated CD19+CD27− naive human B cells. Although stimulation of CD19+ B cells via CD40 alone induced γ1 and γ3 germline transcripts, as well as the expression of activation-induced cytidine deaminase, only stimulation with both anti-CD40 mAb and rIL-21 resulted in the production of Sγ/Sμ switch circular DNA. These results show that IL-21, in addition to promoting growth and differentiation of committed B cells, is a specific switch factor for the production of IgG1 and IgG3.
Amyloid peptide (Aβ) is generated by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (Bace1) and γ-secretase. Aβ production increases after plasma membrane cholesterol loading through unknown mechanisms. To determine how APP-Bace1 proximity affects this phenomenon, we developed a fluorescence lifetime imaging microscopy-Förster resonance energy transfer (FLIM-FRET) technique for visualization of these molecules either by epifluorescence or at the plasma membrane only using total internal reflection fluorescence. Further, we used fluorescence correlation spectroscopy to determine the lipid rafts partition of APP-yellow fluorescent protein (YFP) and Bace1-green fluorescent protein (GFP) molecules at the plasma membrane of neurons. We show that less than 10 min after cholesterol exposure, Bace1-GFP/APP-mCherry proximity increases selectively at the membrane and APP relocalizes to raft domains, preceded by rapid endocytosis. After longer cholesterol exposures, APP and Bace1 are found in proximity intracellularly. We demonstrate that cholesterol loading does not increase Aβ production by having a direct impact on Bace1 catalytic activity but rather by altering the accessibility of Bace1 to its substrate, APP. This change in accessibility is mediated by clustering in lipid rafts, followed by rapid endocytosis.
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