CD25+ CD4+ T Cells Regulate the Expansion of Peripheral CD4 T Cells Through the Production of IL-10 (original) (raw)
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Suppression of CD4+ T Lymphocyte Effector Functions by CD4+CD25+ Cells In Vivo
The Journal of Immunology, 2004
CD4 ؉ CD25 ؉ regulatory T cells have been extensively studied during the last decade, but how these cells exert their regulatory function on pathogenic effector T cells remains to be elucidated. Naive CD4 ؉ T cells transferred into T cell-deficient mice strongly expand and rapidly induce inflammatory bowel disease (IBD). Onset of this inflammatory disorder depends on IFN-␥ production by expanding CD4 ؉ T cells. Coinjection of CD4 ؉ CD25 ؉ regulatory T cells protects recipient mice from IBD. In this study, we show that CD4 ؉ CD25 ؉ regulatory T cells do not affect the initial activation/proliferation of injected naive T cells as well as their differentiation into Th1 effectors. Moreover, naive T cells injected together with CD4 ؉ CD25 ؉ regulatory T cells into lymphopenic hosts are still able to respond to stimuli in vitro when regulatory T cells are removed. In these conditions, they produce as much IFN-␥ as before injection or when injected alone. Finally, when purified, they are able to induce IBD upon reinjection into lymphopenic hosts. Thus, prevention of IBD by CD4 ؉ CD25 ؉ regulatory T cells is not due to deletion of pathogenic T cells, induction of a non reactive state (anergy) among pathogenic effector T cells, or preferential induction of Th2 effectors rather than Th1 effectors; rather, it results from suppression of T lymphocyte effector functions, leading to regulated responses to self.
Journal of Experimental Medicine, 1993
Purified CD4 + lymph node T cells were sorted into two populations on the basis of their expression of CD45RB (CD45RB hi and CD45RB 1~ and injected into congenic severe combined immunodeficient (SCID) mice. After a period of time that was dependent on the number of cells injected, the SCID mice that received CD45RBhi/CD4 + T cells developed a wasting disease that was not seen in SCID mice that received the CD4+/CD45RB 1~ cells or whole lymph node cells. At death, SCID mice that received the CD4 +/CD45RB hi cells had increased spleen and lymph node cellularity compared with normal SCID mice and SCID mice that received the CD4+/CD45RB 1~ T cells. The spleen and lymph node contained CD4 + cells and neither CD8 + nor surface immunoglobulin M-positive cells, plus a population of cells that did not express any of those markers. At necropsy, the SCID mice that received the CD4 +/CD45RB hi cells had significant hyperplasia of the intestinal mucosa with significant lymphoid cell accumulation in the lamina propria. Interestingly, mice that received mixtures of whole lymph node or purified CD4 * cells with CD4 +/CD45RB ~ cells did not develop weight loss, indicating that the unseparated CD4 + population contained cells that were capable of regulating the reactivity of the CD4 +/CD45RB hi cells.
2008
Although the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are mediated through binding and activation of the aryl hydrocarbon receptor (AhR), the subsequent biochemical and molecular changes that confer immune suppression are not well understood. Mice exposed to TCDD during an acute B6-into-B6D2F1 graft-vs-host response do not develop disease, and recently this has been shown to correlate with the generation of CD4 ؉ T cells that express CD25 and demonstrate in vitro suppressive function. The purpose of this study was to further characterize these CD4 ؉ cells (TCDD-CD4 ؉ cells) by comparing and contrasting them with both natural regulatory CD4 ؉ T cells (T-regs) and vehicle-treated cells. Cellular anergy, suppressive functions, and cytokine production were examined. We found that TCDD-CD4 ؉ cells actively proliferate in response to various stimuli but suppress IL-2 production and the proliferation of effector T cells. Like natural T-regs, TCDD-CD4 ؉ cells do not produce IL-2 and their suppressive function is contact dependent but abrogated by costimulation through glucocorticoid-induced TNFR (GITR). TCDD-CD4 ؉ cells also secrete significant amounts of IL-10 in response to both polyclonal and alloantigen stimuli. Several genes were significantly up-regulated in TCDD-CD4 ؉ cells including TGF-3, Blimp-1, and granzyme B, as well as genes associated with the IL12-Rb2 signaling pathway. TCDD-CD4 ؉ cells demonstrated an increased responsiveness to IL-12 as indicated by the phosphorylation levels of STAT4. Only 2% of TCDD-CD4 ؉ cells express Foxp3, suggesting that the AhR does not rely on Foxp3 for suppressive activity. The generation of CD4 ؉ cells with regulatory function mediated through activation of the AhR by TCDD may represent a novel pathway for the induction of T-regs.
The Journal of Immunology
Thymectomy of susceptible strains of mice on day 3 of life results in a spectrum of organ-specific autoimmunity that can be prevented by reconstitution of the thymectomized animals early in life with normal adult lymphocytes. The effectors and suppressors of autoimmunity in this model have been convincingly shown to be CD4+ T cells. It has been demonstrated recently that the regulatory CD4+ T cells that prevent disease coexpress CD25. We have further characterized the population of CD4+CD25+ immunoregulatory cells and demonstrated that they can suppress not only the induction of disease post-thymectomy, but can also efficiently suppress disease induced by cloned autoantigen-specific effector cells. Furthermore, the CD4+CD25+ T cells appear to be members of a unique lineage of regulatory T cells, as the induction of CD25 expression on a monospecific population of T cells derived from TCR transgenic SCID mice did not result in suppression of post-thymectomy autoimmunity. In addition, ...
Regulation of murine chronic colitis by CD4+CD25- programmed death-1+ T cells
European Journal of Immunology, 2005
Naturally arising CD4 + CD25 + regulatory T (T R ) cells are engaged in the maintenance of self tolerance and prevention of autoimmune diseases. However, accumulating evidence suggests that a fraction of peripheral CD4 + CD25 -T cells also possesses regulatory activity. Programmed death-1 (PD-1) is a new member of the CD28/CTLA-4 family, which has been implicated in the maintenance of peripheral self tolerance. Here, we identified a subpopulation of CD4 + CD25 -PD-1 + T cells in the spleen of naive mice that constitutively expressed CTLA-4 and FoxP3 and was hypoproliferative in response to anti-CD3 antibody stimulation in vitro. However, the CD4 + CD25 -PD-1 + T cells uniquely produced large amounts of IL-4 and IL-10 in response to anti-CD3 and anti-CD28 mAb stimulation, unlike the CD4 + CD25 + T R cells. The CD4 + CD25 -PD-1 + T cells exhibited a suppressor activity against the proliferation of anti-CD3 antibody-stimulated CD4 + CD25 -PD-1 -T cells in vitro, which was partially abrogated by anti-CTLA-4 mAb, but not by anti-IL-10 or anti-PD-1 mAb. Remarkably, the CD4 + CD25 -PD-1 + T cells inhibited the development of colitis induced by adoptive transfer of CD4 + CD45RB high T cells into C.B17-scid/scid mice, albeit to a lesser extent than CD4 + CD25 + T R cells, in a CTLA-4-dependent manner. These results indicate that the CD4 + CD25 -PD-1 + T cells contain substantial amounts of T R cells that are involved in the maintenance of peripheral tolerance.
2000
Increased expression of CD40 and CD40 ligand (CD40L or CD154) has been found in inflamed mucosa of human inflammatory bowel disease (IBD), and interactions between these molecules seem to be involved in local cytokine production by macrophages. However, the precise role of CD40 signaling in the pathogenesis of IBD is still poorly understood. The aim of the present study was to investigate the in vivo relevance of CD40 signaling in experimental colitis in SCID mice reconstituted with syngeneic CD45RB high CD4 ؉ T cells. The results demonstrated that CD40 ؉ and CD40L ؉ cells as well as their mRNA levels were significantly increased in inflamed mucosa. Administration of anti-CD40L neutralizing mAb over an 8-wk period starting immediately after CD45RB high CD4 ؉ T cell reconstitution completely prevented symptoms of wasting disease. Intestinal mucosal inflammation was effectively prevented, as revealed by abrogated leukocyte infiltration and decreased CD54 expression and strongly diminished mRNA levels of the proinflammatory cytokines IFN-␥, TNF, and IL-12. When colitic SCID mice were treated with anti-CD40L starting at 5 wk after T cell transfer up to 8 wk, this delayed treatment still led to significant clinical and histological improvement and down-regulated proinflammatory cytokine secretion. These data suggest that the CD40-CD40L interactions are essential for the Th1 inflammatory responses in the bowel in this experimental model of colitis. Blockade of CD40 signaling may be beneficial to human IBD.