Costimulation controls diabetes by altering the balance of pathogenic and regulatory T cells

Bour-Jordan, Hélène; Salomon, Benoı̂t L.; Thompson, Heather L.; Szot, Gregory L.; Bernhard, Matthew R.; Bluestone, Jeffrey A.

doi:10.1172/jci200420483

Cited by 130 publications

(59 citation statements)

References 47 publications

(35 reference statements)

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“…Because some of the same costimulatory signals are needed for stimulation of effector T cells and Treg, a small change in level can alter the balance between these two cell types. CD28 and CD40 have disparate effects on inducing these T cell fates in NOD mice, as a loss of CD28 can restore diabetes in CD40L-deficient mice and alters the number of Tregs in those mice (120). …”

Section: Effects Of DC Maturation Thresholds On Development Of Autoimmentioning

confidence: 99%

“…(134)]. The NOD mouse has been utilized to study several different mechanisms of blocking costimulatory pathways, both genetically and pharmacologically (120, 135, 136). Some of these therapies have been translated for use in type 1 diabetes patients: treatment with CTLA-4-Ig was successful in delaying disease, but was not successful in reversing disease course, with continued loss of C-peptide, a byproduct of insulin processing that is a marker of endogenous insulin production (137, 138).…”

Section: Blocking DC Alterations To Maintain T Cell Tolerancementioning

confidence: 99%

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The Role of Dendritic Cell Subsets and Innate Immunity in the Pathogenesis of Type 1 Diabetes and Other Autoimmune Diseases

Price

Tarbell

2015

Front. Immunol.

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Dendritic cells (DCs) are key antigen-presenting cells that have an important role in autoimmune pathogenesis. DCs control both steady-state T cell tolerance and activation of pathogenic responses. The balance between these two outcomes depends on several factors, including genetic susceptibility, environmental signals that stimulate varied innate responses, and which DC subset is presenting antigen. Although the specific DC phenotype can diverge depending on the tissue location and context, there are four main subsets identified in both mouse and human: conventional cDC1 and cDC2, plasmacytoid DCs, and monocyte-derived DCs. In this review, we will discuss the role of these subsets in autoimmune pathogenesis and regulation, as well as the genetic and environmental signals that influence their function. Specific topics to be addressed include impact of susceptibility loci on DC subsets, alterations in DC subset development, the role of infection- and host-derived innate inflammatory signals, and the role of the intestinal microbiota on DC phenotype. The effects of these various signals on disease progression and the relative effects of DC subset composition and maturation level of DCs will be examined. These areas will be explored using examples from several autoimmune diseases but will focus mainly on type 1 diabetes.

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Section: Effects Of DC Maturation Thresholds On Development Of Autoimmentioning

confidence: 99%

Section: Blocking DC Alterations To Maintain T Cell Tolerancementioning

confidence: 99%

The Role of Dendritic Cell Subsets and Innate Immunity in the Pathogenesis of Type 1 Diabetes and Other Autoimmune Diseases

Price

Tarbell

2015

Front. Immunol.

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“…T-reg can prevent the proliferation of effector T cells through mechanisms that likely include inhibition of cytokine production and of co-stimulatory pathways [36], as well as induction of tryptophan catabolism [37]. To the extent that replication of HIV virus is accelerated by cell division, it seems reasonable that T-reg might therefore limit virus production.…”

Section: Contribution Of Innate and Adaptive Immune Responses To Elitmentioning

confidence: 99%

Th17 cells and regulatory T cells in elite control over HIV and SIV

Hartigan-O’Connor

Hirao

McCune

et al. 2011

Current Opinion in HIV and AIDS

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Purpose of review We present current findings about two subsets of CD4+ T cells that play an important part in the initial host response to infection with the human immunodeficiency virus type 1 (HIV): those producing IL-17 (Th17 cells) and those with immunosuppressive function (CD25+FoxP3+ regulatory T cells, or T-reg). The role of these cells in control of viral infection and immune activation as well as in prevention of immune deficiency in HIV-infected elite controllers will be examined. We will also discuss the use of the simian immunodeficiency virus (SIV)-infected macaque model of AIDS to study the interplay between these cells and lentiviral infection in vivo. Recent Findings Study of Th17 cells in humans and non-human primates (NHP) has shown that depletion of these cells is associated with dissemination of microbial products from the infected gut, increased systemic immune activation, and disease progression. Most impressively, having a smaller Th17 cell compartment has been found to predict these outcomes. T-reg have been associated with reduced antiviral T cell responses but not with suppression of generalized T cell activation. Both cell subsets influence innate immune responses and, in so doing, may shape the inflammatory milieu of the host at infection. Summary Interactions between Th17 cells, T-reg, and cells of the innate immune system influence the course of HIV and SIV infection from its earliest stages, even before the appearance of adaptive immunity. Such interactions may be pivotal for elite control over disease progression.

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“…We previously reported that neuropathy and diabetes occurred with similar kinetics and incidence in NOD-B7-2KO males and females treated with anti-B7-1 mAbs [29,46]. In contrast, we observed a strong gender bias in the development of autoimmunity in NOD-B7-2KO- Idd3 / 5 treated with anti-B7-1 mAbs (Fig.…”

Section: Resultsmentioning

confidence: 55%

“…We previously showed that treatment of NOD-B7-2KO mice with anti-B7-1 mAbs between 2 and 4 wk of age accelerated neuropathy and restored diabetes, reflecting a breakdown in immune regulation likely due to reduced numbers of regulatory T cells (Tregs) [29,46]. Since anti-B7-1-treated NOD-B7-2KO mice develop diabetes and neuropathy with similar incidence and kinetics, we took advantage of this model to compare the influence of Idd3 / 5 and Idd3 / 10 / 18 loci combinations on each disease within the same animal.…”

Section: Resultsmentioning

confidence: 99%

Distinct genetic control of autoimmune neuropathy and diabetes in the non-obese diabetic background

Bour-Jordan

Thompson

Giampaolo

et al. 2013

Journal of Autoimmunity

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The non-obese diabetic (NOD) mouse is susceptible to the development of autoimmune diabetes but also multiple other autoimmune diseases. Over twenty susceptibility loci linked to diabetes have been identified in NOD mice and progress has been made in the definition of candidate genes at many of these loci (termed Idd for insulin-dependent diabetes). The susceptibility to multiple autoimmune diseases in the NOD background is a unique opportunity to examine susceptibility genes that confer a general propensity for autoimmunity versus susceptibility genes that control individual autoimmune diseases. We previously showed that NOD mice deficient for the costimulatory molecule B7-2 (NOD-B7-2KO mice) were protected from diabetes but spontaneously developed an autoimmune peripheral neuropathy. Here, we took advantage of multiple NOD mouse strains congenic for Idd loci to test the role of these Idd loci the development of neuropathy and determine if B6 alleles at Idd loci that are protective for diabetes will also be for neuropathy. Thus, we generated NOD-B7-2KO strains congenic at Idd loci and examined the development of neuritis and clinical neuropathy. We found that the NOD-H-2g7 MHC region is necessary for development of neuropathy in NOD-B7-2KO mice. In contrast, other Idd loci that significantly protect from diabetes did not affect neuropathy when considered individually. However, we found potent genetic interactions of some Idd loci that provided almost complete protection from neuritis and clinical neuropathy. In addition, defective immunoregulation by Tregs could supersede protection by some, but not other, Idd loci in a tissue-specific manner in a model where neuropathy and diabetes occurred concomitantly. Thus, our study helps identify Idd loci that control tissue-specific disease or confer general susceptibility to autoimmunity, and brings insight to the Treg-dependence of autoimmune processes influenced by given Idd region in the NOD background.

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Costimulation controls diabetes by altering the balance of pathogenic and regulatory T cells

Cited by 130 publications

References 47 publications

The Role of Dendritic Cell Subsets and Innate Immunity in the Pathogenesis of Type 1 Diabetes and Other Autoimmune Diseases

The Role of Dendritic Cell Subsets and Innate Immunity in the Pathogenesis of Type 1 Diabetes and Other Autoimmune Diseases

Th17 cells and regulatory T cells in elite control over HIV and SIV

Distinct genetic control of autoimmune neuropathy and diabetes in the non-obese diabetic background

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