Quantification of CD4+T Cell Alloreactivity and Its Control by Regulatory T Cells Using Time-Lapse Microscopy and Immune Synapse Detection

Background/Aims: IL10 is a key inhibitor of effector T cell activation and a mediator of intestinal homeostasis. In addition, IL10 has emerged as a key immunoregulator during infection with various pathogens, ameliorating the excessive T-cell responses that are responsible for much of the immunopathology associated with the infection. Because IL10 plays an important role in both intestinal homeostasis and infection, we studied the function of IL10 in infection-associated intestinal inflammation. Methods: Wildtype mice and mice deficient in CD4+ T cell-derived or regulatory T cells-derived IL10 were infected with the enteric pathogen Citrobacter (C.) rodentium and analyzed for the specific immune response and pathogloy in the colon. Results: We found that IL10 expression is upregulated in colonic tissue after infection with C. rodentium, especially in CD4+ T cells, macrophages and dendritic cells. Whereas the deletion of IL10 in regulatory T cells had no effect on C. rodentium induced colitis, infection of mice deficient in CD4+ T cell-derived IL10 exhibited faster clearance of the bacterial burden but worse colitis, crypt hyperplasia, and pathology than did WT mice. In addition, the depletion of CD4+ T cell-derived IL10 in infected animals was accompanied by an accelerated IFNγ and IL17 response in the colon. Conclusion: Thus, we conclude that CD4+ T cell-derived IL10 is strongly involved in the control of C. rodentium-induced colitis. Interference with this network could have implications for the treatment of infection-associated intestinal inflammation.

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CD4+ T Cell Depletion, Immune Activation and Increased Production of Regulatory T Cells in the Thymus of HIV-Infected Individuals

PLoS ONE ◽

10.1371/journal.pone.0010788 ◽

2010 ◽

Vol 5 (5) ◽

pp. e10788 ◽

Cited By ~ 36

Author(s):

Alessandra Bandera ◽

Giulio Ferrario ◽

Marina Saresella ◽

Ivana Marventano ◽

Alessandro Soria ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Immune Activation ◽

Cd4 T Cell ◽

Cell Depletion ◽

T Cell Depletion

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Imaging of plasmacytoid dendritic cell interactions with T cells

Blood ◽

10.1182/blood-2008-02-139865 ◽

2009 ◽

Vol 113 (1) ◽

pp. 75-84 ◽

Cited By ~ 33

Author(s):

María Mittelbrunn ◽

Gloria Martínez del Hoyo ◽

María López-Bravo ◽

Noa B. Martín-Cofreces ◽

Alix Scholer ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Plasmacytoid Dendritic Cell ◽

Time Lapse ◽

Cell Interactions ◽

Type I ◽

Microtubule Organizing Center ◽

Immune Synapse ◽

Organizing Center

Abstract Plasmacytoid dendritic cells (pDCs) efficiently produce type I interferon and participate in adaptive immune responses, although the molecular interactions between pDCs and antigen-specific T cells remain unknown. This study examines immune synapse (IS) formation between murine pDCs and CD4+ T cells. Mature pDCs formed canonical ISs, involving relocation to the contact site of the microtubule-organizing center, F-actin, protein kinase C-θ, and pVav, and activation of early signaling molecules in T cells. However, immature pDCs were less efficient at forming conjugates with T cells and inducing IS formation, microtubule-organizing center translocation, and T-cell signaling and activation. Time-lapse videomicroscopy and 2-photon in vivo imaging of pDC–T-cell interactions revealed that immature pDCs preferentially mediated transient interactions, whereas mature pDCs promoted more stable contacts. Our data indicate that, under steady-state conditions, pDCs preferentially establish transient contacts with naive T cells and show a very modest immunogenic capability, whereas on maturation, pDCs are able to form long-lived contacts with T cells and significantly enhance their capacity to activate these lymphocytes.

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Suppressive activity of regulatory T cells correlates with high CD4+ T-cell counts and low T-cell activation during chronic simian immunodeficiency virus infection

AIDS ◽

10.1097/qad.0b013e3283437c7b ◽

2011 ◽

Vol 25 (5) ◽

pp. 585-593 ◽

Cited By ~ 6

Author(s):

Ingrid Karlsson ◽

Benoît Malleret ◽

Patricia Brochard ◽

Benoît Delache ◽

Julien Calvo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virus Infection ◽

Regulatory T Cells ◽

T Cell Activation ◽

Cell Activation ◽

Cd4 T Cell ◽

Suppressive Activity ◽

Cell Counts ◽

Immunodeficiency Virus

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Reciprocal CD4+ T-Cell Balance of Effector CD62Llow CD4+ and CD62LhighCD25+ CD4+ Regulatory T Cells in Small Cell Lung Cancer Reflects Disease Stage

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-08-1156 ◽

2008 ◽

Vol 14 (21) ◽

pp. 6770-6779 ◽

Cited By ~ 76

Author(s):

Kenichi Koyama ◽

Hiroshi Kagamu ◽

Satoru Miura ◽

Toru Hiura ◽

Takahiro Miyabayashi ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Small Cell Lung Cancer ◽

Small Cell ◽

Cd4 T Cell ◽

Disease Stage ◽

Small Cell Lung ◽

Cell Balance

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Regulatory T cells are essential to promote proper CD4 T-cell priming upon mucosal infection

Mucosal Immunology ◽

10.1038/mi.2016.19 ◽

2016 ◽

Vol 9 (6) ◽

pp. 1395-1406 ◽

Cited By ~ 18

Author(s):

A G Soerens ◽

A Da Costa ◽

J M Lund

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cd4 T Cell ◽

Mucosal Infection ◽

T Cell Priming

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Antigen targeting to endosomal pathway in dendritic cell vaccination activates regulatory T cells and attenuates tumor immunity

Blood ◽

10.1182/blood-2005-11-008615 ◽

2006 ◽

Vol 108 (4) ◽

pp. 1298-1305 ◽

Cited By ~ 15

Author(s):

Mikael Maksimow ◽

Mari Miiluniemi ◽

Fumiko Marttila-Ichihara ◽

Sirpa Jalkanen ◽

Arno Hänninen

Keyword(s):

T Cells ◽

T Cell ◽

Dendritic Cell ◽

Regulatory T Cells ◽

Antigen Processing ◽

Cd4 T Cell ◽

Cytotoxic T Cell ◽

Dendritic Cell Vaccination ◽

Lymphoma Cells ◽

Self Antigen

Abstract Lymphoma cells are malignant cells of the T- or B-cell lineage that often express many surface markers inappropriately, yet are not recognized as abnormal by the immune system. We modeled this situation by inoculating ovalbumin-expressing E.G7-OVA lymphoma cells into mice that expressed ovalbumin as a self antigen in pancreatic islets, and investigated the efficacy of dendritic cell (DC) vaccination in these mice. Although vaccination with DC-expressing ovalbumin induced strong cytotoxic T-cell immunity, which led to clearance of E.G7-OVA lymphoma cells in naive C57BL/6 mice, DC vaccination was ineffective in mice expressing ovalbumin as a self antigen. Antigen modification to increase its processing via the endosomal processing pathway dramatically increased CD4 T-cell activation but paradoxically, impaired the protective effect of DC vaccination even in naive mice. Depletion of CD25+ T cells (regulatory T cells [Tregs]) prior to vaccination restored the efficacy of DC vaccination and allowed eradication of lymphoma also in mice expressing ovalbumin as a self antigen. We conclude that lymphoma cells may be eradicated using DC vaccination if activation of CD25+ Tregs is simultaneously inhibited, and that intentionally enhanced endosomal antigen processing in DC vaccines may shift the balance from CD4 T-cell help toward stimulation of Tregs.

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Regulatory T Cells Expressing Tumor Necrosis Factor Receptor Type 2 Play a Major Role in CD4+ T-Cell Impairment During Sepsis

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa225 ◽

2020 ◽

Vol 222 (7) ◽

pp. 1222-1234 ◽

Cited By ~ 1

Author(s):

Benjamin J Gaborit ◽

Antoine Roquilly ◽

Cédric Louvet ◽

Abderrahmane Sadek ◽

Benoit Tessoulin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Necrosis Factor ◽

Regulatory T Cells ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Receptor ◽

Cd4 T Cell ◽

Treg Subset ◽

Necrosis Factor

Abstract Sepsis causes inflammation-induced immunosuppression with lymphopenia and alterations of CD4+ T-cell functions that renders the host prone to secondary infections. Whether and how regulatory T cells (Treg) are involved in this postseptic immunosuppression is unknown. We observed in vivo that early activation of Treg during Staphylococcus aureus sepsis induces CD4+ T-cell impairment and increases susceptibility to secondary pneumonia. The tumor necrosis factor receptor 2 positive (TNFR2pos) Treg subset endorsed the majority of effector immunosuppressive functions, and TNRF2 was particularly associated with activation of genes involved in cell cycle and replication in Treg, probably explaining their maintenance. Blocking or deleting TNFR2 during sepsis decreased the susceptibility to secondary infection. In humans, our data paralleled those in mice; the expression of CTLA-4 was dramatically increased in TNFR2pos Treg after culture in vitro with S. aureus. Our findings describe in vivo mechanisms underlying sepsis-induced immunosuppression and identify TNFR2pos Treg as targets for therapeutic intervention.

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