Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity.

Powrie, Fiona; Correa-Oliveira, Rodrigo; Mauze, Smita; Coffman, Robert L.

doi:10.1084/jem.179.2.589

Cited by 581 publications

(384 citation statements)

References 41 publications

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“…It is especially important to consider the possible role of IL-10 produced by CD4 ϩ CD25 ϩ CD45RB low regulatory T cells, as these have recently been shown to be activated in resistant C57BL/6 mice and to suppress the ability of CD4 ϩ CD25 Ϫ CD45RB high cells to effect sterile cure (25). Consistent with their suppressive role in L. major-infected BALB/c mice, removal of the CD4 ϩ CD45RB low subset from splenic cells resulted in the transfer of immunity to L. major-infected scid mice (26). In contrast, anti-CD25 treatment was recently found to exacerbate L. major infection in BALB/c mice (27), suggesting that while regulatory T cells may be activated by L. major, they are not responsible for susceptibility, but actually suppress the Th2 effector cells that are.…”

Section: Discussionmentioning

confidence: 55%

The Relative Contribution of IL-4 Receptor Signaling and IL-10 to Susceptibility toLeishmania major

Noben-Trauth

Lira²,

Nagase

et al. 2003

The Journal of Immunology

111

101

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The roles of IL-10 and IL-4 receptor signaling were evaluated in a murine model of Leishmania major infection. In previous studies the L. major substrain LV39 caused progressive, nonhealing lesions in BALB/c mice deficient for IL-4R α-chain (IL-4Rα), while substrain IR173 was highly controlled. To explore whether IL-10 is responsible for inducing susceptibility to LV39, wild-type and IL-4Rα−/− mice were treated with anti-IL-10R mAb, and in a genetic approach, the IL-4Rα−/− mice were crossed with BALB/c IL-10−/− mice. In contrast to the lack of resistance conferred by IL-4Rα gene deletion, partial resistance to LV39 was conferred by IL-10 gene deletion or treatment of BALB/c mice with anti-IL-10R mAb. Lesion sizes and LV39 parasite numbers were further and dramatically reduced in both anti-IL-10R-treated IL-4Rα−/− mice and IL-4Rα × IL-10 double knockouts. Anti-IL-10R mAb treatment further suppressed parasite growth in IL-4Rα−/− mice infected with L. major IR173. Production of IFN-γ was only increased relative to wild-type or littermate controls in IL-4Rα−/− mice with complementary defects in IL-10. Comparisons of IFN-γ-treated infected macrophages in vitro indicated that LV39 required 25- to 500-fold greater concentrations of IFN-γ than IR173-infected macrophages to achieve a similar efficiency of parasite killing. These studies suggest that regardless of parasite substrain, IL-10 is as important as IL-4/IL-13 in promoting susceptibility to L. major and even more so for those substrains that are relatively resistant to IFN-γ mediated killing.

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Section: Discussionmentioning

confidence: 55%

The Relative Contribution of IL-4 Receptor Signaling and IL-10 to Susceptibility toLeishmania major

Noben-Trauth

Lira²,

Nagase

et al. 2003

The Journal of Immunology

111

101

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“…In the chemically induced mouse model of IBD, such as that induced by acetic acid (AA), dextran sulphate (DSS), or trinitrobezene sulphonic acid (TNBS), a clear Th1 type of cytokine pattern was observed [5][6][7][8]. Similarly, in cell transfer studies, immunodeficient mice reconstituted with CD45RBhigh cells, which predominantly produce IFN-γ upon activation, developed IBD [9][10][11][12]. In addition, CD45RBhigh cells from STAT-4 deficient mice were unable to induce IBD.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory bowel disease requires the interplay between innate and adaptive immune signals

Shi

Das

2006

Cell Res

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Inflammatory bowl disease (IBD) is a type 1 T helper cell (Th1)-mediated autoimmune disease. Various studies have revealed that environmental pathogens also play a significant role in the initiation and progression of this disease. Interestingly, the pathogenesis of IBD has been shown to be related to nitric oxide (NO) released from innate immune cells. Although NO is known to be highly toxic to the gut epithelia, there is very little information about the regulation of NO production, One major question in the etiology of IBD is how Th1 cells and pathogens interact in the induction of IBD. In present study, we focused on the regulation of NO. We show that macrophages require both interferon-γ (IFN-γ)-mediated and TLR4-mediated signals for the production of NO, which causes inflammation in the intestine and subsequently IBD. Thus, IBD is the result of concerted actions of innate immune signals, such as the binding of LPS to TLR-4, and adaptive immune signals, such as IFN-γ produced by Th1 cells.

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“…These data indicate that CD40-CD40L interactions are probably relevant to the pathogenesis of human IBD. To further analyze the role of CD40-CD40L interactions, we used an experimental murine model for colitis, which has been shown to be useful for the investigation of the pathogenesis of human IBD (21)(22)(23)(24). SCID mice are reconstituted with syngeneic CD45RB high CD4 ϩ T cells.…”

Section: Prevention Of Experimental Colitis In Scid Micementioning

confidence: 99%

Prevention of Experimental Colitis in SCID Mice Reconstituted with CD45RBhigh CD4+ T Cells by Blocking the CD40-CD154 Interactions

Liu¹,

Geboes

Colpaert³

et al. 2000

The Journal of Immunology

119

103

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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 CD45RBhighCD4+ 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 CD45RBhighCD4+ 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-γ, 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.

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Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity.

Cited by 581 publications

References 41 publications

The Relative Contribution of IL-4 Receptor Signaling and IL-10 to Susceptibility toLeishmania major

The Relative Contribution of IL-4 Receptor Signaling and IL-10 to Susceptibility toLeishmania major

Inflammatory bowel disease requires the interplay between innate and adaptive immune signals

Prevention of Experimental Colitis in SCID Mice Reconstituted with CD45RBhigh CD4+ T Cells by Blocking the CD40-CD154 Interactions

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