CD4+CD25− T Cells That Express Latency-Associated Peptide on the Surface Suppress CD4+CD45RBhigh-Induced Colitis by a TGF-β-Dependent Mechanism

Oida, Tatsuo; Zhang, Xingmin; Goto, Masao; Hachimura, Satoshi; Totsuka, Mamoru; Kaminogawa, Shuichi; Weiner, Howard L.

doi:10.4049/jimmunol.170.5.2516

Cited by 219 publications

(199 citation statements)

References 38 publications

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“…75 Conversely, TGF-␤ can regulate immunosuppressive regulatory T cells, and TSP1 has been implicated in regulating TGF-␤ activation by regulatory T cells. 76 It remains to be determined whether systemic blockade of TSP1-dependent latent TGF-␤ activation alters immune cell profiles in diabetic animals.…”

Section: Discussionmentioning

confidence: 99%

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Miao

Schoeb

et al. 2011

The American Journal of Pathology

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Transforming growth factor-␤ (TGF-␤) is key in the pathogenesis of diabetic nephropathy. Thrombospondin 1 (TSP1) expression is increased in diabetes, and TSP1 regulates latent TGF-␤ activation in vitro and in diabetic animal models. Herein, we investigate the effect of blockade of TSP1-dependent TGF-␤ activation on progression of renal disease in a mouse model of type 1 diabetes (C57BL/6J-Ins2 Akita ) as a targeted treatment for diabetic nephropathy. Akita and control C57BL/6 mice who underwent uninephrectomy received 15 weeks of thrice-weekly i.p. treatment with 3 or 30 mg/kg LSKL peptide, control SLLK peptide, or saline. The effects of systemic LSKL peptide on dermal wound healing was assessed in type 2 diabetic mice (db/db). Proteinuria (urinary albumin level and albumin/creatinine ratio) was significantly improved in Akita mice treated with 30 mg/kg LSKL peptide. LSKL treatment reduced urinary TGF-␤ activity and renal phospho-Smad2/3 levels and improved markers of tubulointerstitial injury (fibronectin) and podocytes (nephrin). However, LSKL did not alter glomerulosclerosis or glomerular structure. LSKL did not increase tumor incidence or inflammation or impair diabetic wound healing. These data suggest that selective targeting of excessive TGF-␤ activity through blockade of TSP1-dependent TGF-␤ activation represents a therapeutic strategy for treating diabetic nephropathy that preserves the homeostatic functions of TGF-␤.

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Section: Discussionmentioning

confidence: 99%

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Miao

Schoeb

et al. 2011

The American Journal of Pathology

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“…CD103 (integrin § E ) + (CD25 + or CD25 -) § g T R cells that express CTLA-4 protect mice from colitis pointing to CD103 as a marker for a T R cells subset apparently specialized for cross-talk with epithelial cells [13]. Activated, membrane TGF-g -expressing (CD25 + or CD25 -) T R cells suppress the manifestation of transfer colitis [14]. IL-10-producing CD4 + T R1 suppress proliferation of CD4 + T cells in response to antigen and prevent colitis induced in immunodeficient mice by transfer of CD4 + CD45RB hi T cells [15].…”

Section: Introductionmentioning

confidence: 99%

MHC class II‐independent CD25⁺ CD4⁺ CD8α β⁺ α β T cells attenuate CD4⁺ T cell‐induced transfer colitis

2004

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CD4 + § g T cell populations that develop in mice deficient in MHC class II (through 'knockout' of either the A § , or the A g chain of the I-A b molecule) comprise a major 'single-positive' (SP) CD4 + CD8 -subset (60-90%) and a minor 'double-positive' (DP) CD4 + CD8 § g + subset (10-40%). Many DP T cells found in spleen, mesenteric lymph nodes (MLN) and colonic lamina propria (cLP) express CD25, CD103 and Foxp3. Adoptive transfer of SP but not DP T cells from A § -/-or A g -/-B6 mice into congenic RAG -/-hosts induces colitis. Transfer of SP T cells repopulates the host with only SP T cells; transfer of DP T cells repopulates the host with DP and SP T cells. Anti-CD25 antibody treatment of mice transplanted with DP T cells induces severe, lethal colitis; anti-CD25 antibody treatment of mice transplanted with SP T cells further aggravates the course of severe colitis. Hence, regulatory CD25 + T cells within (or developing from) the DP T cell population of MHC class II-deficient mice control the colitogenic potential of CD25 -CD4 + T cells.

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“…One study reported that activated CD4 + CD25 + T cells express an inactive form of TGF-b1 complexed to its latency associated peptide (LAP), a complex hypothesized to account for the enhanced suppressive capacity of activated CD4 + CD25 + T cells in vitro and in vivo [28,29]. On the other hand, Oida et al reported that TGF-bdependent suppression was observed in the LAP + CD4 + CD25 -T cell subset [33]. In addition, some studies have suggested a correlation between Treg effector function and the expression of a latent, membrane-bound form of TGF-b1 on CD4 + CD25 + Treg cells isolated from inflamed lymphoid tissues draining target organs undergoing autoimmune attack [30].…”

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confidence: 99%

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

et al. 2005

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Naturally occurring CD4 + CD25 + regulatory T cells (Treg) are potent suppressors of CD4 + and CD8 + T cell responses in vitro and inhibit several organ-specific autoimmune diseases. While most in vitro studies suggest that CD4 + CD25 + Treg cells adopt a cytokine-independent but cell contact-dependent mode of T cell regulation, their precise mechanism of suppression in vivo remains largely unknown. Here we examine the functional contribution of Treg cell-derived TGF-b1 and effector T cell responsiveness to TGF-b in CD4 + CD25 + T cell-mediated suppression of inflammatory bowel disease (IBD). We show that CD4 + CD25 + Treg cells from either TGF-b1 +/+ or neonatal TGF-b1 -/-mice can suppress the incidence and severity of IBD as well as colonic IFN-c mRNA expression induced by WT CD4 + CD25 -effector T cells. Furthermore, TGF-b-resistant Smad3 -/-CD4 + CD25 + Treg cells are equivalent to WT Treg cells in their capacity to suppress disease induced by either WT or Smad3 -/-CD4 + CD25 -effector T cells. Finally, anti-TGF-b treatment exacerbates the colitogenic potential of CD4 + CD25 -effector T cells in the absence of CD4 + CD25 + Treg cells.Together, these data demonstrate that in certain situations CD4 + CD25 + T cells are able to suppress intestinal inflammation by a mechanism not requiring Treg cell-derived TGF-b1 or effector T cell/Treg cell responsiveness to TGF-b via Smad3. IntroductionCD25 (IL-2Ra chain)-expressing CD4 + T cells, which constitute 5-10% of normal CD4 + T cells, play a critical role in the induction and maintenance of peripheral tolerance [1,2]. These naturally occurring CD4 + CD25 + regulatory T (Treg) cells consist of an anergic lymphocyte population with potent immunosuppressive functions in vivo, as the depletion of CD25-expressing CD4 + T cells correlates with increased immunity to tumors, grafts and intracellular pathogens and provokes the induction of multiple inflammatory diseases including autoimmmune gastritis (AIG) and inflammatory bowel disease (IBD) [3,4]. Currently, the mechanism(s) by which CD4 + CD25 + Treg cells mediate suppression in vitro and in vivo is unclear. Following TCR activation, CD4 + CD25 + Treg cells suppress the in vitro proliferation and cytokine production of CD4 + and CD8 + T cells in an antigen nonspecific, but contact-dependent manner that does not appear to involve modulation of APC function [5][6][7]. The role of regulatory cytokines in CD4 + CD25 + Treg cell control of inflammation in vivo appears to be tissue and/ or context-dependent. While CD4 + CD25 + Treg cells from IL-4 -/-and IL-10 -/-mice are as effective as WT CD4 + CD25 + T cells in mediating suppression of AIG, CD4 + CD25 + Treg cells from IL-10 -/-mice cannot control IBD induced by antigen-experienced effector T cells [8,9]. Similarly, IL-10 -/-CD4 + CD25 + Treg cells, in contrast to WT cells, fail to attenuate effector T cell responses to Leishmania major in resistant C57BL/6 mice [10].TGF-b1 is a potently suppressive cytokine that plays a critical role in the regulation of immune function, a...

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CD4+CD25− T Cells That Express Latency-Associated Peptide on the Surface Suppress CD4+CD45RBhigh-Induced Colitis by a TGF-β-Dependent Mechanism

Cited by 219 publications

References 38 publications

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

MHC class II‐independent CD25⁺ CD4⁺ CD8α β⁺ α β T cells attenuate CD4⁺ T cell‐induced transfer colitis

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation

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CD4+CD25− T Cells That Express Latency-Associated Peptide on the Surface Suppress CD4+CD45RBhigh-Induced Colitis by a TGF-β-Dependent Mechanism

Cited by 219 publications

References 38 publications

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

Blockade of TSP1-Dependent TGF-β Activity Reduces Renal Injury and Proteinuria in a Murine Model of Diabetic Nephropathy

MHC class II‐independent CD25+ CD4+ CD8α β+ α β T cells attenuate CD4+ T cell‐induced transfer colitis

TGF‐β1 production by CD4+CD25+ regulatory T cells is not essential for suppression of intestinal inflammation

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MHC class II‐independent CD25⁺ CD4⁺ CD8α β⁺ α β T cells attenuate CD4⁺ T cell‐induced transfer colitis

TGF‐β1 production by CD4⁺CD25⁺ regulatory T cells is not essential for suppression of intestinal inflammation