Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals

Mayer, Christian T.; Tian, Lei; Hesse, Christina; Kühl, Anja A.; Swallow, Maxine; Kruse, Friederike; Thiele, Mario; Gershwin, M. Eric; Liston, Adrian; Sparwasser, Tim

doi:10.1016/j.jaut.2013.08.010

Cited by 27 publications

(24 citation statements)

References 46 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Conversely, serum alkaline phosphatase was significantly reduced (Fig. D), a phenomenon also observed in scurfy mice . Collectively, these results suggest that adult DEREG × Foxp3 GFP mice rapidly develop autoimmunity and clinically relevant tissue damage after Treg‐cell depletion.…”

Section: Resultssupporting

confidence: 55%

Few Foxp3⁺ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity

et al. 2014

View full text Add to dashboard Cite

Foxp3 specifies the Treg cell lineage and is indispensable for immune tolerance. Accordingly, rare Foxp3 mutations cause lethal autoimmunity. The mechanisms precipitating more prevalent human autoimmune diseases are poorly understood, but involve a combination of genetic and environmental factors. Many autoimmune diseases associate with a partial Treg-cell dysfunction, yet mouse models reflecting such complex pathophysiological processes are rare. Around 95% of Foxp3 + Treg cells can be specifically depleted in bacterial artifical chromosome (BAC)-transgenic Depletion of REGulatory T cells (DEREG) mice through diphtheria toxin (DT) treatment. However, Treg-cell depletion fails to cause autoimmunity in adult DEREG mice for unclear reasons. By crossing Foxp3 GFP knock-in mice to DEREG mice, we introduced additional genetic susceptibility that does not affect untreated mice. Strikingly, DT treatment of DEREG × Foxp3 GFP mice rapidly causes autoimmunity characterized by blepharitis, tissue damage, and autoantibody production. This inflammatory disease is associated with augmented T-cell activation, increased Th2 cytokine production and myeloproliferation, and is caused by defective Treg-cell homeostasis, preventing few DT-insensitive Treg cells from repopulating the niche after Treg-cell depletion. Our study provides important insights into self-tolerance. We further highlight DEREG × Foxp3 GFP mice as a model to investigate the role of environmental factors in precipitating autoimmunity. This may help to better understand and treat human autoimmunity.Keywords: Autoimmunity r DEREG r Scurfy r Treg cellsAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionTreg cells play a principal role in mediating tolerance to selfantigens and both their lineage and function is specifically Correspondence: Dr. Tim Sparwasser e-mail: tim.sparwasser@twincore.de defined by the transcription factor Foxp3 [1][2][3][4][5][6]. Additionally, Treg cells can also negatively regulate appropriate responses against pathogens and tumor cells [7,8]. The scurfy mouse harbours a natural frameshift mutation in the Foxp3 gene resulting in a * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 2990 Immunomodulation 2991 complete loss of Treg-cell function and lethal autoimmunity [9,10]. This mirrors the rare Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome in humans similarly caused by FOXP3 mutations [11]. Impaired Treg-cell function has also been implied in more frequent human autoimmune diseases such as type I diabetes, rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus [12]. However, the mechanisms precipitating and sustaining these prevalent diseases are much less understood and involve both genetic and environmental predisposing factors to varying degrees [13]. DT [19]. Surprisingly, adult DEREG mice show no observable signs of ...

show abstract

Section: Resultssupporting

confidence: 55%

Few Foxp3⁺ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity

et al. 2014

View full text Add to dashboard Cite

show abstract

“…T cell infiltrates including CD4 + and CD8 + T cells are noted in the liver of both patients with PBC and murine models of autoimmune cholangitis [5][6][7]15,18,[25][26][27][28][29][30][31][32]. In this study, 2-OA-BSA/α-GalCer-immunized mice had significant increases in CD4 + and CD8 + T cells.…”

Section: Discussionmentioning

confidence: 52%

Innate immunity drives xenobiotic-induced murine autoimmune cholangitis

Chang

Chen

et al. 2014

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryAlthough primary biliary cirrhosis (PBC) is considered a model autoimmune disease, it has not responded therapeutically to traditional immunosuppressive agents. In addition, PBC may recur following liver transplantation, despite the absence of major histocompatibility complex (MHC) matching, in sharp contrast to the well-known paradigm of MHC restriction. We have suggested previously that invariant natural killer T (iNK T) cells are critical to the initiation of PBC. In this study we have taken advantage of our ability to induce autoimmune cholangitis with 2-octynoic acid, a common component of cosmetics, conjugated to bovine serum albumin (2-OA-BSA), and studied the natural history of pathology in mice genetically deleted for CD4 or CD8 following immunization with 2-OA-BSA in the presence or absence of α-galactosylceramide (α-GalCer). In particular, we address whether autoimmune cholangitis can be induced in the absence of traditional CD4 and CD8 responses. We report herein that CD4 and CD8 knock-out mice immunized with 2-OA-BSA/PBS or 2-OA-BSA/α-GalCer develop anti-mitochondrial antibodies (AMAs), portal infiltrates and fibrosis. Indeed, our data suggest that the innate immunity is critical for immunopathology and that the pathology is exacerbated in the presence of α-GalCer. In conclusion, these data provide not only an explanation for the recurrence of PBC following liver transplantation in the absence of MHC compatibility, but also suggest that effective therapies for PBC must include blocking of both innate and adaptive pathways.

show abstract

“…In CIA, an OX40-blocking FAb fragment which prevented reverse signaling was equaled in efficacy by an OX40L fusion protein previously shown to block OX40L but signal through OX40 [135]. Supporting this argument is the finding that in mice deficient in Treg, the resulting multi-system autoimmunity is more significantly attenuated by OX40 blockade or deficiency than CD4+ and/or CD8+ deficiency [136,137]. Such findings may offer an alternative explanation for studies where apparent OX40 agonists have ameliorated autoimmune disease.…”

Section: Ox40l Blockade May Have More Potent Effects Than Ox40 Blockadementioning

confidence: 95%

OX40, OX40L and Autoimmunity: a Comprehensive Review

Webb

Hirschfield

Lane

2015

Clinic Rev Allerg Immunol

204

159

View full text Add to dashboard Cite

The tumour necrosis factor receptor OX40 (CD134) is activated by its cognate ligand OX40L (CD134L, CD252) and functions as a T cell co-stimulatory molecule. OX40-OX40L interactions have been proposed as a potential therapeutic target for treating autoimmunity. OX40 is expressed on activated T cells, and in the mouse at rest on regulatory T cells (Treg). OX40L is found on antigen-presenting cells, activated T cells and others including lymphoid tissue inducer cells, some endothelia and mast cells. Expression of both molecules is increased after antigen presentation occurs and also in response to multiple other pro-inflammatory factors including CD28 ligation, CD40L ligation and interferon-gamma signaling. Their interactions promote T cell survival, promote an effector T cell phenotype, promote T cell memory, tend to reduce regulatory function, increase effector cytokine production and enhance cell mobility. In some circumstances, OX40 agonism may be associated with increased tolerance, although timing with respect to antigenic stimulus is important. Further, recent work has suggested that OX40L blockade may be more effective than OX40 blockade in reducing autoimmunity. This article reviews the expression of OX40 and OX40L in health, the effects of their interactions and insights from their under- or over-expression. We then review OX40 and OX40L expression in human autoimmune disease, identified associations of variations in their genes (TNFRSF4 and TNFSF4, respectively) with autoimmunity, and data from animal models of human diseases. A rationale for blocking OX40-OX40L interaction in human autoimmunity is then presented along with commentary on the one trial of OX40L blockade in human disease conducted to date. Finally, we discuss potential problems with clinical use of OX40-OX40L directed pharmacotherapy.

show abstract

Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals

Cited by 27 publications

References 46 publications

Few Foxp3⁺ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity

Few Foxp3⁺ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity

Innate immunity drives xenobiotic-induced murine autoimmune cholangitis

OX40, OX40L and Autoimmunity: a Comprehensive Review

Contact Info

Product

Resources

About

Anti-CD4 treatment inhibits autoimmunity in scurfy mice through the attenuation of co-stimulatory signals

Cited by 27 publications

References 46 publications

Few Foxp3+ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity

Few Foxp3+ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity

Innate immunity drives xenobiotic-induced murine autoimmune cholangitis

OX40, OX40L and Autoimmunity: a Comprehensive Review

Contact Info

Product

Resources

About

Few Foxp3⁺ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity

Few Foxp3⁺ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity