Autoimmune-Mediated Intestinal Inflammation–Impact and Regulation of Antigen-Specific CD8+ T Cells

Westendorf, Astrid M.; Fleissner, Diana; Deppenmeier, Stefanie; Gruber, Achim D.; Bruder, Dunja; Hansen, Wiebke; Liblau, Roland; Buer, Jan

doi:10.1053/j.gastro.2006.05.015

Cited by 66 publications

(80 citation statements)

References 50 publications

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“…Therefore, suspicious about the quiescent phenotype of autoaggressive CD8 + T cells, we speculated that these cells might have instead differentiated to a stage of anergy or into Tregs that could in turn contribute to the maintenance of immune tolerance. However, in contrast to the results obtained for CD8 + T cell-mediated intestinal inflammation (40) or CD4 + T lymphocyte-related pulmonary disease (41), lung-specific CD8 + T cells do not differentiate into Foxp3 + Tregs nor do they become anergic, as they proliferate massively upon antigenic stimulation in vitro. Notably, when the autoreactive lymphocytes infiltrating the lung are CD4 + T cells (23,41,42), their fate, function, and phenotype are quite opposite those we observed for CD8 + T cells.…”

Section: Discussioncontrasting

confidence: 96%

CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation

Tosiek

Gruber

Bader

et al. 2011

The Journal of Immunology

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Every person harbors a population of potentially self-reactive lymphocytes controlled by tightly balanced tolerance mechanisms. Failures in this balance evoke immune activation and autoimmunity. In this study, we investigated the contribution of self-reactive CD8+ T lymphocytes to chronic pulmonary inflammation and a possible role for naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) in counterbalancing this process. Using a transgenic murine model for autoimmune-mediated lung disease, we demonstrated that despite pulmonary inflammation, lung-specific CD8+ T cells can reside quiescently in close proximity to self-antigen. Whereas self-reactive CD8+ T cells in the inflamed lung and lung-draining lymph nodes downregulated the expression of effector molecules, those located in the spleen appeared to be partly Ag-experienced and displayed a memory-like phenotype. Because ex vivo-reisolated self-reactive CD8+ T cells were very well capable of responding to the Ag in vitro, we investigated a possible contribution of nTregs to the immune control over autoaggressive CD8+ T cells in the lung. Notably, CD8+ T cell tolerance established in the lung depends only partially on the function of nTregs, because self-reactive CD8+ T cells underwent only biased activation and did not acquire effector function after nTreg depletion. However, although transient ablation of nTregs did not expand the population of self-reactive CD8+ T cells or exacerbate the disease, it provoked rapid accumulation of activated CD103+CD62Llo Tregs in bronchial lymph nodes, a finding suggesting an adaptive phenotypic switch in the nTreg population that acts in concert with other yet-undefined mechanisms to prevent the detrimental activation of self-reactive CD8+ T cells.

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Section: Discussioncontrasting

confidence: 96%

CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation

Tosiek

Gruber

Bader

et al. 2011

The Journal of Immunology

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“…These HA-specific CD4 ϩ T cells (detected by the clonotypic 6.5 mAb) have been described to be "anergic" in terms of in vitro-induced proliferation and secrete significant levels of . It has been shown that the whole CD4 ϩ 6.5 ϩ T cell population isolated from TCR-HA ϫ Ig-HA mice suppressed tissue destruction by naive CD4 ϩ 6.5 ϩ T cells (isolated from TCR-HA mice) (18) and, most recently, we could demonstrate that these CD4 ϩ 6.5 ϩ T R cells are able to reduce wasting disease induced by HA-specific CD8 ϩ T cells in mice expressing the cognate Ag under control of the gut-specific Villin promoter (19). It has been suggested that the specific expression of the cognate Ag by nonactivated APCs in the hemopoietic system in these double-transgenic (dtg) TCR-HA ϫ Ig-HA mice resulted mostly in CD4 ϩ CD25 Ϫ T R cells, which could be differentiated from mature Ag-specific T cells in the absence of a functioning thymus and without tutoring by other T cells (20).…”

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confidence: 77%

“…Most recently, we have demonstrated that the whole CD4 ϩ 6.5 ϩ T cell population isolated from TCR-HA ϫ Ig-HA mice was able to interfere with CD8 ϩ T cell-induced colitis in Villin-HA mice, expressing their cognate Ag under control of the gut-specific Villin promoter (19). However, these experiments were performed with CD4 ϩ 6.5 ϩ T cells irrespective of CD25 expression.…”

Section: Ag-specific Induced Dtg Cd25 ϫ T R Cells Are Able To Controlmentioning

confidence: 99%

Chronic Antigen Stimulation In Vivo Induces a Distinct Population of Antigen-Specific Foxp3−CD25− Regulatory T Cells

Hansen

Westendorf

Reinwald

et al. 2007

The Journal of Immunology

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The concept of immune regulation/suppression has been well-established and, besides thymus-derived CD4+CD25+ regulatory T (TR) cells, it became clear that a variety of additional peripherally induced TR cells play vital roles in protection from many harmful immune responses including intestinal inflammation. In the present study, we have analyzed in vivo-induced Ag-specific CD4+ TR cells with respect to their molecular and functional phenotype. By comparative genomics we could show that these Ag-specific TR cells induced by chronic Ag stimulation in vivo clearly differ in their genetic program from naturally occurring thymus-derived CD4+CD25+ TR cells. This distinct population of induced TR cells express neither CD25 nor the TR-associated transcription factor Foxp3. Strikingly, CD25 is not even up-regulated upon stimulation. Despite the lack in Foxp3 expression, these in vivo-induced CD25− TR cells are able to interfere with an Ag-specific CD8+ T cell-mediated intestinal inflammation without significant increase in CD25 and Foxp3 expression. Thus, our results demonstrate that in vivo-induced Ag-specific TR cells represent a distinct population of Foxp3−CD25− TR cells with regulatory capacity both in vitro and in vivo.

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“…For induction of acute colitis, CD8 + T cells from CL4-TCR transgenic mice that express an α/βT cell receptor recognizing an epitope of the HA protein presented by MHC class I (the H-2Kd:HA512-520 complex) were adoptively transferred into VILLIN-HA mice that express the A/PR8/34 HA epitope from influenza virus A under control of the enterocyte-specific villin promoter (44). Single-cell suspensions were prepared from the spleen of CL4-TCR transgenic mice.…”

Section: Methodsmentioning

confidence: 99%

Gut inflammation can boost horizontal gene transfer between pathogenic and commensal Enterobacteriaceae

Stecher

Denzler

Maier

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The mammalian gut harbors a dense microbial community interacting in multiple ways, including horizontal gene transfer (HGT). Pangenome analyses established particularly high levels of genetic flux between Gram-negative Enterobacteriaceae. However, the mechanisms fostering intraenterobacterial HGT are incompletely understood. Using a mouse colitis model, we found that Salmonella-inflicted enteropathy elicits parallel blooms of the pathogen and of resident commensal Escherichia coli. These blooms boosted conjugative HGT of the colicin-plasmid p2 from Salmonella enterica serovar Typhimurium to E. coli. Transconjugation efficiencies of ∼100% in vivo were attributable to high intrinsic p2-transfer rates. Plasmid-encoded fitness benefits contributed little. Under normal conditions, HGT was blocked by the commensal microbiota inhibiting contact-dependent conjugation between Enterobacteriaceae. Our data show that pathogen-driven inflammatory responses in the gut can generate transient enterobacterial blooms in which conjugative transfer occurs at unprecedented rates. These blooms may favor reassortment of plasmid-encoded genes between pathogens and commensals fostering the spread of fitness-, virulence-, and antibiotic-resistance determinants.bacterial evolution | hospital-acquired infection | mucosal immune response | plasmid spread

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Autoimmune-Mediated Intestinal Inflammation–Impact and Regulation of Antigen-Specific CD8+ T Cells

Cited by 66 publications

References 50 publications

CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation

CD4+CD25+Foxp3+ Regulatory T Cells Are Dispensable for Controlling CD8+ T Cell-Mediated Lung Inflammation

Chronic Antigen Stimulation In Vivo Induces a Distinct Population of Antigen-Specific Foxp3−CD25− Regulatory T Cells

Gut inflammation can boost horizontal gene transfer between pathogenic and commensal Enterobacteriaceae

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