Tolerance of activated pathogenic CD4+ T cells by transcriptional targeting of dendritic cells

AbstractTissue mononuclear phagocytes (MNP) are specialised in pathogen detection and antigen presentation. As such they deliver HIV to its primary target cells; CD4 T cells. Most MNP HIV transmission studies have focused on epithelial MNPs. However, as mucosal trauma and inflammation are now known to be strongly associated with HIV transmission, here we examine the role of sub-epithelial MNPs which are present in a diverse array of subsets. We show that HIV can penetrate the epithelial surface to interact with sub-epithelial resident MNPs in anogenital explants and define the full array of subsets that are present in the human anogenital and colorectal tissues that HIV may encounter during sexual transmission. In doing so we identify two subsets that preferentially take up HIV, become infected and transmit the virus to CD4 T cells; CD14+CD1c+ monocyte-derived dendritic cells and langerin-expressing conventional dendritic cells 2 (cDC2).

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Splenic Stroma-Educated Regulatory Dendritic Cells Induce Apoptosis of Activated CD4 T Cells via Fas Ligand-Enhanced IFN-γ and Nitric Oxide

The Journal of Immunology ◽

10.4049/jimmunol.1101696 ◽

2011 ◽

Vol 188 (3) ◽

pp. 1168-1177 ◽

Cited By ~ 14

Author(s):

Xiongfei Xu ◽

Hai Yi ◽

Zhenhong Guo ◽

Cheng Qian ◽

Sheng Xia ◽

...

Keyword(s):

Nitric Oxide ◽

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Fas Ligand ◽

Ifn Γ ◽

Regulatory Dendritic Cells

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Enhanced proliferation of CD4+ T cells induced by dendritic cells following antigen uptake in the presence of specific antibody

Veterinary Immunology and Immunopathology ◽

10.1016/0165-2427(95)05478-2 ◽

1996 ◽

Vol 49 (4) ◽

pp. 321-330 ◽

Cited By ~ 9

Author(s):

S. Coughlan ◽

G.D. Harkiss ◽

J. Hopkins

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Specific Antibody ◽

Cd4 T Cells ◽

Antigen Uptake

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Human Dendritic Cells Stimulated via TLR7 and/or TLR8 Induce the Sequential Production of Il-10, IFN-γ, and IL-17A by Naive CD4+ T Cells

The Journal of Immunology ◽

10.4049/jimmunol.0801969 ◽

2009 ◽

Vol 182 (6) ◽

pp. 3372-3379 ◽

Cited By ~ 74

Author(s):

Vincent Lombardi ◽

Laurence Van Overtvelt ◽

Stéphane Horiot ◽

Philippe Moingeon

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Ifn Γ ◽

Human Dendritic Cells

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Dexamethasone Preconditioning Improves the Response of Collagen-Induced Arthritis to Treatment with Short-Term Lipopolysaccharide-Stimulated Collagen-Loaded Dendritic Cells

Clinical and Developmental Immunology ◽

10.1155/2013/296031 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Corina Peña ◽

David Gárate ◽

Juan Contreras-Levicoy ◽

Octavio Aravena ◽

Diego Catalán ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd4 T Cells ◽

Combined Treatment ◽

Type Ii Collagen ◽

Cytokine Profile ◽

Clinical Disease ◽

Type Ii ◽

Collagen Induced Arthritis ◽

Short Term

Background. Pharmacologically modulated dendritic cells (DCs) have been shown to restore tolerance in type II collagen-(CII-) induced arthritis (CIA). We examined the effect of dexamethasone (DXM) administration as a preconditioning agent, followed by an injection of lipopolysaccharide-(LPS-) stimulated and CII-loaded DCs on the CIA course.Methods. After CIA induction, mice pretreated with DXM were injected with 4-hour LPS-stimulated DCs loaded with CII (DXM/4hLPS/CII/DCs).Results. Mice injected with DXM/4hLPS/CII/DCs displayed significantly less severe clinical disease compared to animals receiving 4hLPS/CII/DCs alone or those in which only DXM was administered. Cytokine profile evaluation showed that CD4+ T cells from DXM/4hLPS/CII/DCs and 4hLPS/CII/DCs groups release higher IL-10 levels than those from mice receiving DXM alone or CIA mice. CD4+ T cells from all DC-treated groups showed less IL-17 release when compared to the CIA group. On the contrary, CD4+ T cells from DXM/4hLPS/CII/DCs and 4hLPS/CII/DCs groups released higher IFN-γlevels than those from CIA group.Conclusion. A combined treatment, including DXM preconditioning followed by an inoculation of short-term LPS-stimulated CII-loaded DCs, provides an improved strategy for attenuating CIA severity. Our results suggest that this benefit is driven by a modulation in the cytokine profile secreted by CD4+ T cells.

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The proliferative response of CD4 T cells to steady-state CD8+ dendritic cells is restricted by post-activation death

International Immunology ◽

10.1093/intimm/dxh382 ◽

2006 ◽

Vol 18 (3) ◽

pp. 415-423 ◽

Cited By ~ 14

Author(s):

Alexandra Rizzitelli ◽

Edwin Hawkins ◽

Hilary Todd ◽

Philip D. Hodgkin ◽

Ken Shortman

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Steady State ◽

Cd4 T Cells ◽

Proliferative Response

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Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements.

Journal of Experimental Medicine ◽

10.1084/jem.176.5.1431 ◽

1992 ◽

Vol 176 (5) ◽

pp. 1431-1437 ◽

Cited By ~ 156

Author(s):

M Croft ◽

D D Duncan ◽

S L Swain

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd4 Cells ◽

Peptide Antigen ◽

Naive T Cells ◽

Naïve T Cells ◽

Antigen Presenting

Because of the low frequency of T cells for any particular soluble protein antigen in unprimed animals, the requirements for naive T cell responses in specific antigens have not been clearly delineated and they have been difficult to study in vitro. We have taken advantage of mice transgenic for the V beta 3/V alpha 11 T cell receptor (TCR), which can recognize a peptide of cytochrome c presented by IEk. 85-90% of CD4+ T cells in these mice express the transgenic TCR, and we show that almost all such V beta 3/V alpha 11 receptor-positive cells have a phenotype characteristic of naive T cells, including expression of high levels of CD45RB, high levels of L-selectin (Mel-14), low levels of CD44 (Pgp-1), and secretion of interleukin 2 (IL-2) as the major cytokine. Naive T cells, separated on the basis of CD45RB high expression, gave vigorous responses (proliferation and IL-2 secretion) to peptide antigen presented in vitro by a mixed antigen-presenting cell population. At least 50% of the T cell population appeared to respond, as assessed by blast transformation, entry into G1, and expression of increased levels of CD44 by 24 h. Significant contributions to the response by contaminating memory CD4+ cells were ruled out by demonstrating that the majority of the CD45RB low, L-selectin low, CD44 high cells did not express the V beta 3/V alpha 11 TCR and responded poorly to antigen. We find that proliferation and IL-2 secretion of the naive CD4 cells is minimal when resting B cells present peptide antigen, and that both splenic and bone marrow-derived macrophages are weak stimulators. Naive T cells did respond well to high numbers of activated B cells. However, dendritic cells were the most potent stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers. These studies establish that naive CD4 T cells can respond vigorously to soluble antigen and indicate that maximal stimulation can be achieved by presentation of antigen on dendritic cells. This model should prove very useful in further investigations of activation requirements and functional characteristics of naive helper T cells.

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Abstract 129: Suppressor of Cytokine Signaling 1 in Dendritic Cells Inhibits Myocardial Inflammation in Experimental Autoimmune Myocarditis

Circulation Research ◽

10.1161/res.111.suppl_1.a129 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Kazuko Tajiri ◽

Kyoko Imanaka-Yoshida ◽

Michiaki Hiroe ◽

Nobutake Shimojo ◽

Satoshi Sakai ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cytokine Signaling ◽

Autoimmune Myocarditis ◽

Dc Function ◽

Autoreactive T Cell ◽

Experimental Autoimmune Myocarditis ◽

Experimental Autoimmune

Introduction: Autoimmunity is considered to play an important role in the development of myocarditis and dilated cardiomyopathy. Recent reports have indicated that a subgroup of myocarditis patients may benefit from immune-targeted therapies. Suppressor of cytokine signaling1 (SOCS1) is an intracellular, cytokine-inducible protein that regulates the responses of immune cells to cytokines. We therefore hypothesized that overexpression of SOCS1 may inhibit the inflammation of myocarditis and cardiomyopathy. Methods and Results: Myocarditis was induced by subcutaneous immunization with cardiac specific peptides derived from α-myosin heavy chain in BALB/c mice on days 0 and 7. Plasmid DNA encoding SOCS1 (pSOCS1) was injected intraperitoneally into mice on days 0, 5 and 10. pSOCS1 treatment significantly decreased heart-to-body weight ratios and the number of infiltrating cells in the heart. Echocardiography showed preserved contractile function in pSOCS1-treated mice. Although autoimmune myocarditis is a CD4+ T cell-mediated disease, pSOCS1 treatment does not have a direct suppressive effect on autoreactive T-cell activation. The introduced pSOCS1 suppressed proinflammatory cytokine production and STAT1 phosphorylation in dendritic cells (DCs). In addition, the proliferative responses of autoreactive CD4+ T cells co-cultured with DCs from pSOCS1-treated mice were much weaker than those of cells cultured with DCs from control plasmid-injected mice. These results suggested that the inoculated pSOCS1 may have been transfected into DCs and impaired DC function in vivo. Conclusion: The administration of pSOCS1 protected mice from the development of experimental autoimmune myocarditis, which was mediated by the inhibition of DC function that in turn reduced the activation of autoreactive CD4+ T cells.

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