CD134L Expression on Dendritic Cells in the Mesenteric Lymph Nodes Drives Colitis in T Cell-Restored SCID Mice

Malmström, Vivianne; Shipton, D; Singh, Baljit; Al‐Shamkhani, Aymen; Puklavec, M J; Barclay, A. Neil; Powrie, Fiona

doi:10.4049/jimmunol.166.11.6972

Cited by 188 publications

(150 citation statements)

References 59 publications

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“…The next reasonable question to pose during C. neoformans infection would therefore be why the endogenous natural interaction between OX40 and OX40L does not result in the same effect in the absence of the fusion protein. OX40L expression, although constitutive on cardiac myocytes (39) and a subset of dendritic cells in SCID mice (40), is limiting in the absence of a danger signal. Studies detailing the ability of infections to provide a sufficient OX40L-inducing signal to the APC are limiting.…”

Section: Discussionmentioning

confidence: 99%

OX40 Ligation on Activated T Cells Enhances the Control ofCryptococcus neoformansand Reduces Pulmonary Eosinophilia

Humphreys

Edwards

Walzl

et al. 2003

The Journal of Immunology

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Pulmonary eosinophilia induced in C57BL/6 mice after Cryptococcus neoformans infection is driven by CD4+ Th2 cells. The immunological mechanisms that protect against eosinophilia are not fully understood. Interaction of OX40 (CD134) and its ligand, OX40L, has been implicated in T cell activation and cell migration. Unlike CD28, OX40 is only expressed on T cells 1–2 days after Ag activation. Manipulation of this pathway would therefore target recently activated T cells, leaving the naive repertoire unaffected. In this study, we show that engagement of OX40 by an OX40L:Ig fusion protein drives IFN-γ production by CD4+ T cells and reduces eosinophilia and C. neoformans burden in the lung. Using gene-depleted mice, we show that reduction of eosinophilia and pathogen burden requires IL-12 and/or IFN-γ. C. neoformans infection itself only partially induces OX40L expression by APCs. Provision of exogenous OX40L reveals a critical role of this pathway in the prevention of C. neoformans-induced eosinophilia.

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Section: Discussionmentioning

confidence: 99%

OX40 Ligation on Activated T Cells Enhances the Control ofCryptococcus neoformansand Reduces Pulmonary Eosinophilia

Humphreys

Edwards

Walzl

et al. 2003

The Journal of Immunology

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“…Results and discussion CD103 1 DC lose tolerogenic properties during colitis DC, through their ability to prime naïve T cells in MLN and produce inflammatory cytokines, have been implicated in T-cell-mediated colitis [2]. In mice with intestinal inflammation, there was a threefold increase in the total number of CD11c high MHCII high DC in MLN compared with non-colitic mice (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…It is now well established that DC play a central role in orchestrating intestinal immune responses through promotion of inflammatory pathways and the maintenance of tolerance [1][2][3]. Precisely, how DC mediate these diverse and opposing functions is not known.…”

Section: Introductionmentioning

confidence: 99%

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Laffont¹,

Siddiqui²,

2010

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Intestinal CD103 1 DC promote the differentiation of Foxp3 1 Treg from naïve CD4 1 T cells through mechanisms involving TGF-b and the dietary metabolite, retinoic acid (RA). In this study, we have analysed whether the specialised features of CD103 1 DC are conserved in colitis. Our results show that inflammation dampens the tolerogenic properties of MLN CD103 1 DC, which is associated with lower expression of tgfb2 and aldh1a2. Accordingly, CD103 1 DC taken from colitic mice are impaired in their ability to induce Foxp3 1 Treg and instead favour the emergence of IFN-c-producing CD4 1 T cells compared with their steady-state counterparts. BrdU-labelling studies and analysis of ontogeny markers show that CD103 1 DC from steady-state and colitic settings retain similar subset composition and developmental pathways. These results indicate that MLN CD103 1 DC are not hard-wired to promote tolerance but can adapt to environmental conditions. The inflammatory properties of MLN CD103 1 DC in colitic mice may reflect defective gut tolerogenic conditioning or altered migratory pathways and raise the possibility that migratory DC populations contribute to the pathogenesis of inflammatory bowel disease.Key words: Colitis . DC . Intestinal immunity . Ontogeny . Treg IntroductionThe intestinal immune system must maintain a fine balance between harmless responses to food and commensal bacteria and protective immunity to invading pathogens. It is now well established that DC play a central role in orchestrating intestinal immune responses through promotion of inflammatory pathways and the maintenance of tolerance [1][2][3]. Precisely, how DC mediate these diverse and opposing functions is not known. One possibility is that these activities are mediated by distinct DC populations and indeed many subtypes of DC have been identified in the gut [4]. It has been proposed that resident gutconditioned DC may favour tolerogenic responses, whereas newly recruited inflammatory DC may drive host protective immunity.Alternatively, tissue-resident DC may adopt distinct functions under homeostatic and inflammatory conditions [4,5].We and others [6][7][8][9] have identified and characterised a specialised population of MLN DC that express the integrin a E chain, CD103. CD103 1 DC represent a sentinel DC population in the small intestine (SI) and can migrate to the MLN to initiate adaptive immune responses [10]. Under homeostatic conditions, CD103 1 DC in MLN promote the development of Foxp3 1 Treg. By contrast, the reciprocal CD103 À MLN DC population displays a more pro-inflammatory phenotype and appears to represent a developmentally distinct DC population [9].In intestinal inflammation, immune regulatory pathways that normally promote tolerance in the intestine break down. Whether this is attributable to changes in DC populations or their function in the MLN is not known. Here, we show that in colitic mice, the tolerogenic properties of CD103 1 MLN DC are lost and that this APC population now drives inflammatory T-cell responses that may c...

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“…It has recently been suggested that OX40L costimulation may be tied to the function of regulatory T cells (37). We performed several experiments to test whether a difference in the regulatory populations might account for the effect of OX40L on development of autoimmune diabetes.…”

Section: No Detectable Regulatory Cell Defect In the Absence Of Ox40lmentioning

confidence: 99%

Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand

Martín‐Orozco

Chen

Poirot

et al. 2003

The Journal of Immunology

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Costimulatory signals received by diabetogenic T cells during priming by or upon secondary encounter with autoantigen are decisive in determining the outcome of autoimmune attack. The OX40-OX40 ligand (OX40L) costimulatory pathway is known to influence T cell responses, prompting us to examine its role in autoimmune diabetes. A null allele at OX40L completely prevented diabetes development in nonobese diabetic mice and strongly reduced its incidence in a TCR transgenic model (BDC2.5). However, somewhat paradoxically, the initial activation of T cells responsive to islet β cell Ag was slightly faster and more efficient in the absence of OX40L, with an increased degree of cell proliferation and survival in the deficient hosts. Activated T cell migration into and retention within the islets was also slightly accelerated. When challenged in vitro, splenocytes from BDC2.5.OX40Lo/o mice showed no altered reactivity to exogenously added peptide, no bias to the Th1 or Th2 phenotype, and no alteration in T cell survival. Thus, the OX40/OX40L axis has the paradoxical effect of dampening the early activation and migration of autoimmune T cells, but sustains the long-term progression to autoimmune destruction.

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CD134L Expression on Dendritic Cells in the Mesenteric Lymph Nodes Drives Colitis in T Cell-Restored SCID Mice

Cited by 188 publications

References 59 publications

OX40 Ligation on Activated T Cells Enhances the Control ofCryptococcus neoformansand Reduces Pulmonary Eosinophilia

OX40 Ligation on Activated T Cells Enhances the Control ofCryptococcus neoformansand Reduces Pulmonary Eosinophilia

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand

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CD134L Expression on Dendritic Cells in the Mesenteric Lymph Nodes Drives Colitis in T Cell-Restored SCID Mice

Cited by 188 publications

References 59 publications

OX40 Ligation on Activated T Cells Enhances the Control ofCryptococcus neoformansand Reduces Pulmonary Eosinophilia

OX40 Ligation on Activated T Cells Enhances the Control ofCryptococcus neoformansand Reduces Pulmonary Eosinophilia

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells

Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand

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Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells