scholarly journals T cells instruct dendritic cells to produce inflammasome independent IL-1β causing systemic inflammation

2018 ◽  
Author(s):  
Aakanksha Jain ◽  
Ricardo A. Irizarry-Caro ◽  
Amanpreet S. Chawla ◽  
Naomi H. Philip ◽  
Kaitlin R. Carroll ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Systemic Inflammation ◽  
Cd4 T Cells ◽  
Mechanistic Explanation ◽  
Receptor Activation ◽  
Cd4 T Cell ◽  
Inflammasome Activation ◽  
Autoimmune Pathology

AbstractWhile IL-1β is critical for anti-microbial host defense, it is also a key mediator of autoimmune inflammation. Inflammasome activation following pathogenic insults is known to result in IL-1β production. However, the molecular events that produce IL-1β during T cell driven autoimmune diseases remain unclear. Here, we have discovered an inflammasome-independent pathway of IL-1β production that is triggered upon cognate interactions between dendritic cells and effector CD4 T cells. Analogous to inflammasome activation, this “T cell-instructed IL-1β also relies on two independent signaling events. TNFα produced by activated CD4 T cells engages TNFR signaling on DCs leading to pro-IL-1β synthesis. Subsequently, FasL, also expressed by effector CD4 T cells, engages Fas on DCs leading to caspase-8 dependent pro-IL-1β cleavage. Remarkably, this two-step mechanism is completely independent of pattern recognition receptor activation. IL-1β produced upon cognate DC-effector CD4 T cell interaction causes wide spread leukocyte infiltration, a hallmark of systemic inflammation as well as autoimmune pathology. This study has uncovered a novel feature of DC-T cell cross-talk that allows for active IL-1β secretion independent of innate sensing pathways and provides a mechanistic explanation for IL-1β production and its downstream consequences in CD4 T cell driven autoimmune pathology.

scholarly journals Contact-dependent delivery of IL-2 by dendritic cells to CD4 T cells in the contraction phase promotes their long-term survival

2019 ◽  
Vol 11 (2) ◽  
pp. 108-123
Author(s):  
Dan Tong ◽  
Li Zhang ◽  
Fei Ning ◽  
Ying Xu ◽  
Xiaoyu Hu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Immune Memory ◽  
Term Survival

Abstract Common γ chain cytokines are important for immune memory formation. Among them, the role of IL-2 remains to be fully explored. It has been suggested that this cytokine is critically needed in the late phase of primary CD4 T cell activation. Lack of IL-2 at this stage sets for a diminished recall response in subsequent challenges. However, as IL-2 peak production is over at this point, the source and the exact mechanism that promotes its production remain elusive. We report here that resting, previously antigen-stimulated CD4 T cells maintain a minimalist response to dendritic cells after their peak activation in vitro. This subtle activation event may be induced by DCs without overt presence of antigen and appears to be stronger if IL-2 comes from the same dendritic cells. This encounter reactivates a miniature IL-2 production and leads a gene expression profile change in these previously activated CD4 T cells. The CD4 T cells so experienced show enhanced reactivation intensity upon secondary challenges later on. Although mostly relying on in vitro evidence, our work may implicate a subtle programing for CD4 T cell survival after primary activation in vivo.

scholarly journals Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells

2003 ◽  
Vol 198 (2) ◽  
pp. 235-247 ◽  
Author(s):  
Sayuri Yamazaki ◽  
Tomonori Iyoda ◽  
Kristin Tarbell ◽  
Kara Olson ◽  
Klara Velinzon ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Antigen Processing ◽  
Specific Antigen ◽  
Cell Receptor ◽  
Cd4 T Cell

An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T cells that suppress other CD25− autoimmune disease–inducing T cells. The antigen-presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells remain to be identified, hampering their study in experimental and clinical situations. CD25+ CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can proliferate in the absence of added cytokines in culture and in vivo when stimulated by antigen-loaded dendritic cells (DCs), especially mature DCs. With high doses of DCs in culture, CD25+ CD4+ and CD25− CD4+ populations initially proliferate to a comparable extent. With current methods, one third of the antigen-reactive T cell receptor transgenic T cells enter into cycle for an average of three divisions in 3 d. The expansion of CD25+ CD4+ T cells stops by day 5, in the absence or presence of exogenous interleukin (IL)-2, whereas CD25− CD4+ T cells continue to grow. CD25+ CD4+ T cell growth requires DC–T cell contact and is partially dependent upon the production of small amounts of IL-2 by the T cells and B7 costimulation by the DCs. After antigen-specific expansion, the CD25+ CD4+ T cells retain their known surface features and actively suppress CD25− CD4+ T cell proliferation to splenic APCs. DCs also can expand CD25+ CD4+ T cells in the absence of specific antigen but in the presence of exogenous IL-2. In vivo, both steady state and mature antigen-processing DCs induce proliferation of adoptively transferred CD25+ CD4+ T cells. The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses.

scholarly journals Plasmacytoid dendritic cells have divergent effects on HIV infection of initial target cells and induce a pro-retention phenotype

2021 ◽  
Vol 17 (4) ◽  
pp. e1009522
Author(s):  
Orion Tong ◽  
Gabriel Duette ◽  
Thomas Ray O’Neil ◽  
Caroline M. Royle ◽  
Hafsa Rana ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Reverse Transcriptase ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Target Cells ◽  
Ccr5 Expression ◽  
Memory Cd4 T Cells

Although HIV infection inhibits interferon responses in its target cells in vitro, interferon signatures can be detected in vivo soon after sexual transmission, mainly attributed to plasmacytoid dendritic cells (pDCs). In this study, we examined the physiological contributions of pDCs to early HIV acquisition using coculture models of pDCs with myeloid DCs, macrophages and the resting central, transitional and effector memory CD4 T cell subsets. pDCs impacted infection in a cell-specific manner. In myeloid cells, HIV infection was decreased via antiviral effects, cell maturation and downregulation of CCR5 expression. In contrast, in resting memory CD4 T cells, pDCs induced a subset-specific increase in intracellular HIV p24 protein expression without any activation or increase in CCR5 expression, as measured by flow cytometry. This increase was due to reactivation rather than enhanced viral spread, as blocking HIV entry via CCR5 did not alter the increased intracellular p24 expression. Furthermore, the load and proportion of cells expressing HIV DNA were restricted in the presence of pDCs while reverse transcriptase and p24 ELISA assays showed no increase in particle associated reverse transcriptase or extracellular p24 production. In addition, PDCs also markedly induced the expression of CD69 on infected CD4 T cells and other markers of CD4 T cell tissue retention. These phenotypic changes showed marked parallels with resident memory CD4 T cells isolated from anogenital tissue using enzymatic digestion. Production of IFNα by pDCs was the main driving factor for all these results. Thus, pDCs may reduce HIV spread during initial mucosal acquisition by inhibiting replication in myeloid cells while reactivating latent virus in resting memory CD4 T cells and retaining them for immune clearance.

scholarly journals MHC Class II Expression Restricted to CD8α+ and CD11b+ Dendritic Cells Is Sufficient for Control of Leishmania major

2004 ◽  
Vol 199 (5) ◽  
pp. 725-730 ◽  
Author(s):  
Maria P. Lemos ◽  
Fatima Esquivel ◽  
Phillip Scott ◽  
Terri M. Laufer
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Cd4 T Cell ◽  
Major Infection ◽  
Mhc Ii ◽  
Antigen Presenting

Control of the intracellular protozoan, Leishmania major, requires major histocompatibility complex class II (MHC II)–dependent antigen presentation and CD4+ T cell T helper cell 1 (Th1) differentiation. MHC II–positive macrophages are a primary target of infection and a crucial effector cell controlling parasite growth, yet their function as antigen-presenting cells remains controversial. Similarly, infected Langerhans cells (LCs) can prime interferon (IFN)γ–producing Th1 CD4+ T cells, but whether they are required for Th1 responses is unknown. We explored the antigen-presenting cell requirement during primary L. major infection using a mouse model in which MHC II, I-Aβb, expression is restricted to CD11b+ and CD8α+ dendritic cells (DCs). Importantly, B cells, macrophages, and LCs are all MHC II–negative in these mice. We demonstrate that antigen presentation by these DC subsets is sufficient to control a subcutaneous L. major infection. CD4+ T cells undergo complete Th1 differentiation with parasite-specific secretion of IFNγ. Macrophages produce inducible nitric oxide synthase, accumulate at infected sites, and control parasite numbers in the absence of MHC II expression. Therefore, CD11b+ and CD8α+ DCs are not only key initiators of the primary response but also provide all the necessary cognate interactions for CD4+ T cell Th1 effectors to control this protozoan infection.

Regulatory dendritic cells program generation of interleukin-4–producing alternative memory CD4 T cells with suppressive activity

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1218-1227 ◽  
Author(s):  
Xiongfei Xu ◽  
Zhenhong Guo ◽  
Xueyu Jiang ◽  
Yushi Yao ◽  
Qiangguo Gao ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Interleukin 4 ◽  
Delayed Type Hypersensitivity ◽  
Regulatory Function

Abstract The heterogeneity and mechanisms for the generation of CD4 memory T (CD4 Tm) cells remain elusive. Distinct subsets of dendritic cells (DCs) have been found to regulate a distinct T-helper (Th)–cell subset differentiation by influencing cytokine cues around CD4 T cells; however, whether and how the regulatory DC subset can regulate Tm-cell differentiation remains unknown. Further, there is no ideal in vitro experimental system with which to mimic the 3 phases of the CD4 T-cell immune response (expansion, contraction, memory generation) and/or to culture CD4 Tm cells for more than a month. By analyzing CD4 T cells programmed by long-term coculture with regulatory DCs, we identified a population of long-lived CD4 T cells with a CD44hiCD62L−CCR7− effector memory phenotype and rapid, preferential secretion of the Th2 cytokines interleukin-4 (IL-4), IL-5, IL-10, and IL-13 after antigenic stimulation. These regulatory DC-programmed Tm cells suppress CD4 T-cell activation and proliferation in vitro via IL-10 and inhibit the delayed-type hypersensitivity response once infused in vivo. We also identify their natural counterpart, which is up-regulated by regulatory DC transfusion and negatively regulates the recall response in vivo. Different from interferon-γ–producing conventional Tm cells, these IL-4–producing CD4 Tm cells act as alternative Tm cells with a regulatory function, suggesting a new way of negative immune regulation by memory T cells.

Two Photon Intravital Microscopy Reveals CD4+ T Cells Making Cognate Interactions With Tissue Dendritic Cells In Skin Graft-Versus-Host-Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2004-2004
Author(s):  
Sarah Morin-Zorman ◽  
Christian Wysocki ◽  
Edwina Kisanga ◽  
David Gonzalez ◽  
David Rothstein ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Graft Versus Host ◽  
Two Photon

Abstract Graft-versus-host disease (GVHD) limits the broader application of allogeneic hematopoietic stem cell transplantation. In prior studies we defined roles for both host and donor-derived antigen presenting cells (APCs) in the activation of alloreactive donor T cells and promotion of GVHD. While initial T cell activation in GVHD occurs predominantly in secondary lymphoid organs (SLO), we have consistently observed MHCII+ donor-derived tissue APCs (t-APCs), including tissue dendritic cells (t-DCs) in histopathologic GVHD lesions, frequently adjacent to infiltrating T cells. We hypothesize that productive interactions occur between donor APCs and T cells in situ in GVHD target tissues, which propagate disease locally. We could not use knockout or APC depletion approaches to study T cell: t-APCs interactions as they impact APCs systemically and might therefore affect T cell stimulation in SLO. We therefore utilized two-photon intravital microscopy to analyze interactions between fluorescent donor CD4+ T cells and t-DCs in skin. 129 (H-2b) hosts were irradiated and reconstituted with B6 (H-2b) CD11c-YFP transgenic (Tg) Bone Marrow (BM) with B6 RFP Tg CD4 cells and nonfluorescent B6 CD8 cells. We imaged ear skin in GVHD mice 4 weeks later. In general CD4 cells co-localized with DCs. We observed CD4+ T cells that were highly motile and only in transient contact with DCs and others that made stable contact with DCs. To determine how much TCR: MHCII interactions drive sustained CD4+ T cell: DC interactions and arrest CD4+ T cell motility, mice were imaged and then injected with an MHCII blocking antibody (Ab; Y3P) with continued imaging of the same regions. After injection, T cell mean speed significantly increased and the proportion of T cells in stable contact with DCs decreased, indicating that transient disruption of TCR: MHCII is sufficient to restore motility to some T cells. In a second approach to assess the specificity of CD4+ T cell: t-DC interactions we transplanted 129 mice with B6 RFP+ CD4 cells, nonfluorescent CD8 cells and a mix of CD11c-YFP MHCII-/- and RFP wt BM or a mix of CD11c-YFP wt and RFP Tg MHCII-/- BM. We are currently comparing the motility of CD4 cells that make contact with MHCII+ as compared to MHCII- DCs, with the prediction that contact times will be shorter with the latter. Our data suggest that CD4+ T cells make cognate interactions with t-DCs in skin and we hypothesize that these interactions promote GVHD locally. Because the graft-versus-leukemia effect occurs primarily in bone marrow and secondary lymphoid tissues, targeting of tissue-infiltrating APCs could represent a unique strategy to ameliorate GVHD while preserving GVL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Lymph node stromal cells acquire peptide–MHCII complexes from dendritic cells and induce antigen-specific CD4+ T cell tolerance

2014 ◽  
Vol 211 (6) ◽  
pp. 1153-1166 ◽  
Author(s):  
Juan Dubrot ◽  
Fernanda V. Duraes ◽  
Lambert Potin ◽  
Francesca Capotosti ◽  
Dale Brighouse ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Node ◽  
T Cell ◽  
Stromal Cells ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Functions ◽  
Mhcii Expression ◽  
Lymph Node Stromal Cells

Dendritic cells (DCs), and more recently lymph node stromal cells (LNSCs), have been described to tolerize self-reactive CD8+ T cells in LNs. Although LNSCs express MHCII, it is unknown whether they can also impact CD4+ T cell functions. We show that the promoter IV (pIV) of class II transactivator (CIITA), the master regulator of MHCII expression, controls endogenous MHCII expression by LNSCs. Unexpectedly, LNSCs also acquire peptide–MHCII complexes from DCs and induce CD4+ T cell dysfunction by presenting transferred complexes to naive CD4+ T cells and preventing their proliferation and survival. Our data reveals a novel, alternative mechanism where LN-resident stromal cells tolerize CD4+ T cells through the presentation of self-antigens via transferred peptide–MHCII complexes of DC origin.

scholarly journals CD4+ T Cell Polarization in Mice Is Modulated by Strain-specific Major Histocompatibility Complex–independent Differences within Dendritic Cells

2003 ◽  
Vol 198 (2) ◽  
pp. 201-209 ◽  
Author(s):  
Christophe Filippi ◽  
Stéphanie Hugues ◽  
Julie Cazareth ◽  
Valérie Julia ◽  
Nicolas Glaichenhaus ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Leishmania Major ◽  
Inbred Mice ◽  
Cell Polarization ◽  
Cd4 T Cell ◽  
Effector Cells ◽  
Th1 And Th2 Responses

Resistance and susceptibility to Leishmania major in mice are determined by multiple genes and correlate with the preferential development of Th1 and Th2 responses, respectively. Here, we found that CD11b+ dendritic cells (DCs) prime parasite-specific CD4+ T cells in both susceptible BALB/c (H2-d) and resistant B10.D2 (H2-d) mice. However, BALB/c and B10.D2 DCs from L. major–infected mice differ in their ability to polarize naive T cells into Th1 or Th2 effector cells. This difference is cell-intrinsic, is not restricted to H2-d mice, and is observed with both parasite-specific and allospecific CD4+ T cells. Thus, strain-specific differences within CD11b+ DCs influence the ability of inbred mice to mount polarized CD4+ T cell responses.

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