scholarly journals Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity

2009 ◽  
Vol 206 (3) ◽  
pp. 549-559 ◽  
Author(s):  
Caspar Ohnmacht ◽  
Andrea Pullner ◽  
Susan B.S. King ◽  
Ingo Drexler ◽  
Stefanie Meier ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Steady State ◽  
Cd4 T Cells ◽  
Tolerance Induction ◽  
Immunological Tolerance ◽  
Peripheral Tissues ◽  
Reduced Body ◽  
Self Tolerance ◽  
Single Positive

Lack of immunological tolerance against self-antigens results in autoimmune disorders. During onset of autoimmunity, dendritic cells (DCs) are thought to be critical for priming of self-reactive T cells that have escaped tolerance induction. However, because DCs can also induce T cell tolerance, it remains unclear whether DCs are required under steady-state conditions to prevent autoimmunity. To address this question, we crossed CD11c-Cre mice with mice that express diphtheria toxin A (DTA) under the control of a loxP-flanked neomycin resistance (neoR) cassette from the ROSA26 locus. Cre-mediated removal of the neoR cassette leads to DTA expression and constitutive loss of conventional DCs, plasmacytoid DCs, and Langerhans cells. These DC-depleted (ΔDC) mice showed increased frequencies of CD4 single-positive thymocytes and infiltration of CD4 T cells into peripheral tissues. They developed spontaneous autoimmunity characterized by reduced body weight, splenomegaly, autoantibody formation, neutrophilia, high numbers of Th1 and Th17 cells, and inflammatory bowel disease. Pathology could be induced by reconstitution of wild-type (WT) mice with bone marrow (BM) from ΔDC mice, whereas mixed BM chimeras that received BM from ΔDC and WT mice remained healthy. This demonstrates that DCs play an essential role to protect against fatal autoimmunity under steady-state conditions.

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

2006 ◽  
Vol 18 (3) ◽  
pp. 415-423 ◽  
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

scholarly journals Anergy into T regulatory cells: an integration of metabolic cues and epigenetic changes at the Foxp3 conserved non-coding sequence 2

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1938 ◽  
Author(s):  
Milagros Silva Morales ◽  
Daniel Mueller
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
T Regulatory Cells ◽  
Immune Cell ◽  
Tolerance Induction ◽  
Short Review ◽  
Treg Cells ◽  
Peripheral Tolerance ◽  
Protective Mechanisms ◽  
Self Tolerance

Peripheral immune self-tolerance relies on protective mechanisms to control autoreactive T cells that escape deletion in the thymus. Suppression of autoreactive lymphocytes is necessary to avoid autoimmunity and immune cell–mediated damage of healthy tissues. An intriguing relationship has emerged between two mechanisms of peripheral tolerance—induction of anergy and Foxp3+ regulatory T (Treg) cells—and is not yet well understood. A subpopulation of autoreactive anergic CD4 T cells is a precursor of Treg cells. We now hypothesize that phenotypic and mechanistic features of Treg cells can provide insights to understand the mechanisms behind anergy-derived Treg cell differentiation. In this short review, we will highlight several inherent similarities between the anergic state in conventional CD4 T cells as compared with fully differentiated natural Foxp3+ Treg cells and then propose a model whereby modulations in metabolic programming lead to changes in DNA methylation at the Foxp3 locus to allow Foxp3 expression following the reversal of anergy.

scholarly journals Tolerance induction in memory CD4 T cells is partial and reversible

2020 ◽  
Author(s):  
Joshua I Gray ◽  
Shaima Al-Khabouri ◽  
Fraser Morton ◽  
Eric T Clambey ◽  
Laurent Gapin ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Tolerance Induction ◽  
Peripheral Tissues ◽  
Repair Enzymes ◽  
Memory Cd4 T Cells ◽  
Secondary Lymphoid Organs ◽  
Secondary Activation ◽  
Low Expression

AbstractMemory T cells respond rapidly in part because they are less reliant on heightened levels of costimulatory molecules. This presents challenges to silencing memory T cells in tolerance strategies for autoimmunity or allergy. We find that memory CD4 T cells generated by infection or immunisation survive secondary activation with antigen delivered without adjuvant, regardless of their location in secondary lymphoid organs or peripheral tissues. These cells were, however, functionally altered following a tertiary immunisation with antigen and adjuvant, proliferating poorly but maintaining their ability to produce inflammatory cytokines. Transcriptional and cell cycle analysis of these memory CD4 T cells suggest they are unable to commit fully to cell division potentially because of low expression of DNA repair enzymes. In contrast, these memory CD4 T cells could proliferate following tertiary reactivation by viral re-infection. These data suggest that tolerance induction in memory CD4 T cells is partial and can be reversed.

Ligation of TLR5 by Flagellin Converts Tolerogenic Dendritic Cells into Activating Dendritic Cells through Inhibition of IL-10 Production.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2314-2314
Author(s):  
Ildefonso Vicente-Suarez ◽  
Eduardo M. Sotomayor
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Antigen Presentation ◽  
Cd4 T Cells ◽  
Inflammatory Cytokine ◽  
Tolerance Induction ◽  
Unexpected Finding ◽  
Ifn Gamma ◽  
Novel Approach ◽  
Tolerogenic Dcs

Abstract Antigen presentation by DCs differentiated in the presence of the anti-inflammatory cytokine IL-10 has been shown to result in the development of regulatory T cells (Tregs) and tolerance induction. Whether this outcome could be reverted -or not- through manipulation of the tolerogenic DCs (tol-DCs) has not been explored in detail. Here we report for the first time that tol-DCs differentiated in the presence of IL-10 display increased expression of TLR5 as compared with bone marrow-derived DCs differentiated in the presence of GM-CSF and IL-4 (BM-DCs). The increased expression of TLR5 in tol-DCs seems to be a unique characteristic given that expression of other TLRs such as TLR4 and TLR9 was not different in tol-DCs as compared to BM-DCs. In lieu of our previous observation that the TLR5 ligand, flagellin, inhibits IL-10 production in antigen-presenting cells (APCs)1, and the unexpected finding that tol-DCs display higher expression of TLR5, we asked next whether flagellin could influence the functional properties of tol-DCs. First, unlike BM-DCs, tol-DCs stimulated with LPS (TLR4 ligand) produced high levels of IL-10. In sharp contrast, tol-DCs stimulated with flagellin do not produce IL-10 but produce significant levels of the pro-inflammatory cytokine IL-12. Second, while antigen presentation by LPS-stimulated tol-DCs results in the generation of IL-10 producing CD4+ T-cells, presentation of cognate antigen by flagellin-stimulated tol-DCs resulted in CD4+ T-cells that secrete IFN-gamma but not IL-10. This divergent T-cell outcome in response to antigen-presentation by tol-DCs stimulated with LPS (IL-10 producing T-cells) versus flagellin (IFN-gamma producing T-cells) suggests that TLR5 engagement might be a novel approach to convert tolerogenic DCs into activating DCs and effectively trigger productive immune responses in environments that are otherwise conducive to unresponsiveness due to the presence of IL-10.

Efficient priming of protein antigen–specific human CD4+ T cells by monocyte-derived dendritic cells

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3490-3498 ◽  
Author(s):  
Katia Schlienger ◽  
Nancy Craighead ◽  
Kelvin P. Lee ◽  
Bruce L. Levine ◽  
Carl H. June
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Interleukin 12 ◽  
Cd40 Ligation ◽  
Peripheral Tissues ◽  
Tnf Α

Dendritic cells (DCs) have the unique ability to initiate an immune response in vivo by capturing antigens (Ags) in peripheral tissues and migrating to secondary lymphoid organs, where they sensitize naive CD4+ T cells. To mimic this process in vitro, previous studies have shown that DCs directly isolated from peripheral blood can be used to elicit primary responses to neoantigens (neoAgs). In other studies, when monocyte-derived DCs have been utilized to sensitize total CD4+ T cells in vitro, only secondary proliferation to neoAgs could be elicited. In the present study, the relative abilities of CD40 ligation, protein kinase C activation, and culture in tumor necrosis factor α (TNF-α) to induce functional and phenotypic maturation of human DCs from monocyte precursors were compared. Optimal TNF-α–induced maturation of DCs required a prolonged 4-day culture. It was then found that loading immature DCs with the neoAgs keyhole limpet hemocyanin or human immunodeficiency virus-1 p24 gag prior to TNF-α–induced maturation, rather than after maturation, was crucial to sensitize CD4+ T cells to new Ags. This primary proliferation to neoAgs was initiated from the CD4+ CD45RA+naive T-cell population. Finally, it was found that monocyte-derived DCs acquired the ability to secrete interleukin-12 p70, after contact with Ag-specific T cells. The ability to prime and expand Ag-specific CD4+ T cells ex vivo to neoAgs in serum-free conditions has potential application for cellular vaccination and adoptive immunotherapy.

Efficient priming of protein antigen–specific human CD4+ T cells by monocyte-derived dendritic cells

Blood ◽  
2000 ◽  
Vol 96 (10) ◽  
pp. 3490-3498 ◽  
Author(s):  
Katia Schlienger ◽  
Nancy Craighead ◽  
Kelvin P. Lee ◽  
Bruce L. Levine ◽  
Carl H. June
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Interleukin 12 ◽  
Cd40 Ligation ◽  
Peripheral Tissues ◽  
Tnf Α

Abstract Dendritic cells (DCs) have the unique ability to initiate an immune response in vivo by capturing antigens (Ags) in peripheral tissues and migrating to secondary lymphoid organs, where they sensitize naive CD4+ T cells. To mimic this process in vitro, previous studies have shown that DCs directly isolated from peripheral blood can be used to elicit primary responses to neoantigens (neoAgs). In other studies, when monocyte-derived DCs have been utilized to sensitize total CD4+ T cells in vitro, only secondary proliferation to neoAgs could be elicited. In the present study, the relative abilities of CD40 ligation, protein kinase C activation, and culture in tumor necrosis factor α (TNF-α) to induce functional and phenotypic maturation of human DCs from monocyte precursors were compared. Optimal TNF-α–induced maturation of DCs required a prolonged 4-day culture. It was then found that loading immature DCs with the neoAgs keyhole limpet hemocyanin or human immunodeficiency virus-1 p24 gag prior to TNF-α–induced maturation, rather than after maturation, was crucial to sensitize CD4+ T cells to new Ags. This primary proliferation to neoAgs was initiated from the CD4+ CD45RA+naive T-cell population. Finally, it was found that monocyte-derived DCs acquired the ability to secrete interleukin-12 p70, after contact with Ag-specific T cells. The ability to prime and expand Ag-specific CD4+ T cells ex vivo to neoAgs in serum-free conditions has potential application for cellular vaccination and adoptive immunotherapy.

scholarly journals Steady-state migrating intestinal dendritic cells induce potent inflammatory responses in naive CD4+T cells

2008 ◽  
Vol 2 (2) ◽  
pp. 156-165 ◽  
Author(s):  
S W F Milling ◽  
C D Jenkins ◽  
U Yrlid ◽  
V Cerovic ◽  
H Edmond ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Steady State ◽  
Cd4 T Cells ◽  
Inflammatory Responses
Sign in / Sign up

Export Citation Format

Share Document