scholarly journals Inflammasome activation leads to cDC1-independent cross-priming of CD8 T cells by epithelial cell derived antigen

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Katherine A Deets ◽  
Randilea Nichols Doyle ◽  
Isabella Rauch ◽  
Russell E Vance
Keyword(s):  
T Cells ◽  
Immune System ◽  
Epithelial Cell ◽  
Cd8 T Cells ◽  
Innate Immune System ◽  
Antigen Expression ◽  
Genetic System ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Cross Presentation

The innate immune system detects pathogens and initiates adaptive immune responses. Inflammasomes are central components of the innate immune system, but whether inflammasomes provide sufficient signals to activate adaptive immunity is unclear. In intestinal epithelial cells (IECs), inflammasomes activate a lytic form of cell death called pyroptosis, leading to epithelial cell expulsion and the release of cytokines. Here we employed a genetic system to show that simultaneous antigen expression and inflammasome activation specifically in IECs is sufficient to activate CD8+ T cells. By genetic elimination of direct T cell priming by IECs, we found that IEC-derived antigens are cross-presented to CD8+ T cells. However, cross-presentation of IEC-derived antigen to CD8+ T cells only partially depended on IEC pyroptosis. In the absence of inflammasome activation, cross-priming of CD8+ T cells required Batf3+ dendritic cells (cDC1), whereas cross-priming in the presence of pyroptosis required a Zbtb26+ but Batf3-independent cDC population. These data suggest the existence of parallel pyroptosis-dependent and pyroptosis-independent pathways for cross-presentation of IEC-derived antigens.

scholarly journals Pyroptosis-dependent and -independent cross-priming of CD8+ T cells by intestinal epithelial cell-derived antigen

2021 ◽  
Author(s):  
Katherine A Deets ◽  
Randilea D Nichols ◽  
Isabella Rauch ◽  
Russell E Vance
Keyword(s):  
T Cells ◽  
Immune System ◽  
Epithelial Cell ◽  
Innate Immune System ◽  
Antigen Expression ◽  
Genetic System ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Intestinal Epithelial ◽  
Cross Presentation

The innate immune system detects pathogens and initiates adaptive immune responses. Inflammasomes are central components of the innate immune system, but whether inflammasomes provide sufficient signals to activate adaptive immunity is unclear. In intestinal epithelial cells (IECs), inflammasomes activate a lytic form of cell death called pyroptosis, leading to epithelial cell expulsion and the release of cytokines. Here we employed a genetic system to show that simultaneous antigen expression and inflammasome activation specifically in IECs is sufficient to activate CD8+ T cells. By genetic elimination of direct T cell priming by IECs, we found that IEC-derived antigens are cross-presented to CD8+ T cells. However, activation of CD8+ T cells by IEC-derived antigen only partially depended on IEC pyroptosis. In the absence of inflammasome activation, cross-priming of CD8+ T cells required Batf3+ dendritic cells (cDC1), whereas cross-priming in the presence of pyroptosis did not. These data suggest the existence of parallel pyroptosis-dependent and pyroptosis-independent but cDC1-dependent pathways for cross-presentation of IEC-derived antigens.

scholarly journals Adaptive and innate immune cell responses in tendons and lymph nodes after tendon injury and repair

2020 ◽  
Vol 128 (3) ◽  
pp. 473-482 ◽  
Author(s):  
Andrew C. Noah ◽  
Thomas M. Li ◽  
Leandro M. Martinez ◽  
Susumu Wada ◽  
Jacob B. Swanson ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Immune System ◽  
Innate Immune System ◽  
Immune Cell ◽  
Tendon Healing ◽  
Tendon Injury ◽  
Innate Immune ◽  
Adaptive Immune ◽  
Immune Cell Response

Tendon injuries are a common clinical condition with limited treatment options. The cellular components of the innate immune system, such as neutrophils and macrophages, have been studied in tendon injuries. However, the adaptive immune system, comprising specialized lymphocytes, plays an important role in orchestrating the healing of numerous tissues, but less is known about these cells in tendon healing. To gain a greater understanding of the biological processes that regulate tendon healing, we determined how the cellular components of the adaptive and innate immune system respond to a tendon injury using two-month-old male mice. We observed that lymphatic vasculature is present in the epitenon and superficial regions of Achilles tendons, and that the lymphatics drain into the popliteal lymph node. We then created an acute Achilles tenotomy followed by repair, and collected tendons and popliteal lymph nodes 1, 2, and 4 wk after injury. Tendon injury resulted in a robust adaptive immune cell response that followed an initial innate immune cell response in tendons and lymph nodes. Monocytes, neutrophils, and macrophages initially accumulated at 1 wk after injury in tendons, while dendritic cells and CD4+ T cells peaked at 2 wk after injury. B cells and CD8+ T cells progressively increased over time. In parallel, immune cells of the popliteal lymph node demonstrated a similarly coordinated response to the injury. These results suggest that there is an adaptive immune response to tendon injury, and adaptive immune cells may play a role in regulating tendon healing. NEW & NOTEWORTHY While the innate immune system, consisting of macrophages and related hematopoietic cells, has been studied in tendon injury, less is known about the adaptive immune system. Using a mouse model of Achilles tendon tenotomy and repair, we observed an adaptive immune cell response, consisting of CD4+ and CD8+ T cells, and B cells, which occur through 4 wk after tendon injury. This response appeared to be coordinated by the draining popliteal lymph node.

A Critical Role for Innate Immunity In Allogeneic Hematopoietic Cell Rejection Via the TLR4/TRIF Pathway

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 77-77
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Ziqiang Zhu ◽  
Yiming Huang ◽  
Yujie Wen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Innate Immunity ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Innate Immune System ◽  
Critical Role ◽  
Innate Immune ◽  
Wild Type

Abstract Abstract 77 Adaptive immunity, especially T cells, has long been believed to be the dominant immune barrier in allogeneic transplantation. Targeting host T cells significantly reduces conditioning for bone marrow cell (BMC) engraftment. Innate immunity has been recently shown to pose a significant barrier in solid organ transplantation, but has not been addressed in bone marrow transplantation (BMT). Using T cell deficient (TCR-β/δ−/−) or T and B cell deficient (Rag−/−) mice, we found that allogeneic BMC rejection occurred early before the time required for T cell activation and was T- and B-cell independent, suggesting an effector role for innate immune cells in BMC rejection. Therefore, we hypothesized that by controlling both innate and adaptive immunity, the donor BMC would have a window of advantage to engraft. Survival of BMC in vivo was significantly improved by depleting recipient macrophages and/or NK cells, but not neutrophils. Moreover, depletion of macrophages and NK cells in combination with co-stimulatory blockade with anti-CD154 and rapamycin as a novel form of conditioning resulted in 100% allogeneic engraftment without any irradiation and T cell depletion. Donor chimerism remained stable and durable up to 6 months. Moreover, specific Vβ5½ and Vβ11 clonal deletion was detected in host CD4+ T cells in chimeras, indicating central tolerance to donor alloantigens. Whether and how the innate immune system recognizes or responds to allogeneic BMCs remains unknown. Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. The signaling function of TLR depends on intracellular adaptors. The adaptor MyD88 transmits signals emanating from all TLR, except TLR3 while TRIF specifically mediates TLR3 and TLR4 signaling via type 1 IFN. To further determine the innate signaling pathways in allogeneic BMC rejection, B6 background (H2b) MyD88−/− and TRIF−/− mice were conditioned with anti-CD154/rapamycin plus 100 cGy total body irradiation and transplanted with 15 × 106 BALB/c (H2d) BMC. Only 33.3% of MyD88−/− recipients engrafted at 1 month, resembling outcomes for wild-type B6 mice. In contrast, 100% of TRIF−/− mice engrafted. The level of donor chimerism in TRIF−/− mice was 5.1 ± 0.6% at one month, significantly higher than in MyD88−/− and wild-type B6 controls (P < 0.005). To determine the mechanism of innate signaling in BMC rejection, we examined whether TRIF linked TLR3 or TLR4 is the key pattern recognition receptor involved in BMC recognition. To this end, TLR3−/− and TLR4−/− mice were transplanted with BALB/c BMC with same conditioning. None of the TLR3−/− mice engrafted. In contrast, engraftment was achieved in 100% of TLR4−/− mice up to 6 months follow up. Taken together, these results suggest that rejection of allogeneic BMC is uniquely dependent on the TLR4/TRIF signaling pathway. Thus, our results clearly demonstrate a previously unappreciated role for innate immunity in allogeneic BMC rejection. Our current findings are distinct from prior reports demonstrating a critical role of MyD88 in rejection of allogeneic skin grafts and lung, and may reflect unique features related to BMC. The findings of the role of innate immunity in BMC rejection would lead to revolutionary changes in our understanding and management of BMT. This would be informative in design of more specific innate immune targeted conditioning proposals in BMT to avoid the toxicity. Disclosures: Bozulic: Regenerex LLC: Employment. Ildstad:Regenerex LLC: Equity Ownership.

scholarly journals Imbalance of Peripheral Lymphocyte Subsets in Patients With Ankylosing Spondylitis: A Meta-Analysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Dong Liu ◽  
Budian Liu ◽  
Churong Lin ◽  
Jieruo Gu
Keyword(s):  
T Cells ◽  
Immune System ◽  
Ankylosing Spondylitis ◽  
Subgroup Analysis ◽  
Cd4 T Cells ◽  
Innate Immune System ◽  
Lymphocyte Subsets ◽  
Meta Analysis ◽  
Innate Immune ◽  
Healthy Controls

Ankylosing spondylitis is a complicated consequence of genetic predisposition and environmental factors. Enthesitis is believed to be the hallmark of ankylosing spondylitis, and the chronic inflammatory state of this disease is perpetuated by the disturbances of both the innate immune system and the acquired immune system. To clarify the alteration of immune system in patients with AS, we conducted a meta-analysis concerning the proportions of major lymphocyte subsets in the peripheral blood of AS patients. We systematically searched PubMed and China National Knowledge Infrastructure (CNKI) for articles related to this subject. A total of 95 articles involving 4,020 AS patients and 3,065 healthy controls were included in the analysis. This meta-analysis is performed on R platform using R package “meta”, and Egger’s tests were used to determine the presence of publication bias. Results showed that the percentages of T cells, NK cells and NKT cells were not significantly different between AS patients and healthy controls, but B cells were significantly increased. Among the subsets of T cells, the proportions of CD4+ T cells, Th17 cells, Tfh cells as well as Th1/Th2 ratio were significantly increased, while Tregs were significantly decreased. Subgroup analysis showed that the proportions of Th17 among both PBMCs, T cells and CD4+ T cells were significantly elevated, while Tregs were only significantly lower in PBMCs. Subgroup analysis also demonstrated that Tregs defined by “CD4+CD25+FoxP3+”, “CD4+CD25+CD127low”or “CD4+CD25+CD127-”were significantly downregulated, indicating that the selection of markers could be critical. Further study is warranted in order to elucidate the complicated interactions between different lymphocyte subsets in AS patients. This study implied that the disequilibrium between Th17 and Tregs, as well as between Th1 and Th2 could contribute to the pathogenesis of ankylosing spondylitis, further cementing the understanding that ankylosing spondylitis is a consequence of disrupted balance of innate immune system and acquired immune system.

scholarly journals Plasmacytoid and conventional dendritic cells cooperate in crosspriming AAV capsid-specific CD8+ T cells

Blood ◽  
2017 ◽  
Vol 129 (24) ◽  
pp. 3184-3195 ◽  
Author(s):  
Geoffrey L. Rogers ◽  
Jamie L. Shirley ◽  
Irene Zolotukhin ◽  
Sandeep R. P. Kumar ◽  
Alexandra Sherman ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Innate Immune ◽  
Viral Capsid ◽  
Viral Dna ◽  
Cross Presentation ◽  
Key Points ◽  
In Trans ◽  
Immune Sensing ◽  
Innate Immune Sensing

Key Points Crosspriming of AAV capsid-specific CD8+ T cells requires cooperation between distinct subsets of DCs. Innate immune sensing of the viral DNA genome induces cross-presentation of viral capsid in trans.

scholarly journals Flagellar Motility Is a Key Determinant of the Magnitude of the Inflammasome Response to Pseudomonas aeruginosa

2013 ◽  
Vol 81 (6) ◽  
pp. 2043-2052 ◽  
Author(s):  
Yash R. Patankar ◽  
Rustin R. Lovewell ◽  
Matthew E. Poynter ◽  
Jeevan Jyot ◽  
Barbara I. Kazmierczak ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Immune System ◽  
Innate Immune System ◽  
Innate Immune ◽  
Bacterial Motility ◽  
Inflammasome Activation ◽  
Flagellar Motility ◽  
Content Type

ABSTRACTWe previously demonstrated that bacterial flagellar motility is a fundamental mechanism by which host phagocytes bind and ingest bacteria. Correspondingly, loss of bacterial motility, consistently observed in clinical isolates from chronicPseudomonas aeruginosainfections, enables bacteria to evade association and ingestion ofP. aeruginosaby phagocytes bothin vitroandin vivo. Since bacterial interactions with the phagocyte cell surface are required for type three secretion system-dependent NLRC4 inflammasome activation byP. aeruginosa, we hypothesized that reduced bacterial association with phagocytes due to loss of bacterial motility, independent of flagellar expression, will lead to reduced inflammasome activation. Here we report that inflammasome activation is reduced in response to nonmotileP. aeruginosa. NonmotileP. aeruginosaelicits reduced IL-1β production as well as caspase-1 activation by peritoneal macrophages and bone marrow-derived dendritic cellsin vitro. Importantly, nonmotileP. aeruginosaalso elicits reduced IL-1β levelsin vivoin comparison to those elicited by wild-typeP. aeruginosa. This is the first demonstration that loss of bacterial motility results in reduced inflammasome activation and antibacterial IL-1β host response. These results provide a critical insight into how the innate immune system responds to bacterial motility and, correspondingly, how pathogens have evolved mechanisms to evade the innate immune system.

216 Anti-tumor activity of iosH2 by blocking LILRB2 receptor signalling

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A235-A235
Author(s):  
Osiris Marroquin Belaunzaran ◽  
Anahita Rafiei ◽  
Anil Kumar ◽  
Julia Kolibaba ◽  
Lorenz Vogt ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Innate Immune System ◽  
Cell Activation ◽  
Innate Immune ◽  
High Affinity ◽  
Anti Tumor Activity

BackgroundThe human leukocyte immunoglobulin-like receptor family B (LILR B) acts as check point blockade of the innate immune system by inhibiting leukocyte activation through SHP phosphatase recruitment. Some of the physiological ligands include classical HLA class I molecules, including beta-2-microglobulin (B2M) free open conformers (OC). Natural HLA-OC expression is known from autoimmune disease leading to immune activation by pleiotropic effects since they bind to LILRB and KIR family members reducing Treg and MDSC numbers and increased effector T-cell and NK-cell activation, respectively. We have generated an IgG4-HLA-57 open conformer (OC) molecule (iosH2) with high affinity for LILRB molecules and demonstrate its anti-cancer activity in vitro and in vivo.Methods iosH2 was produced by transient gene expression in CHO cells and purified by standard chromatography. Affinity of iosH2 binding was quantified by ELISA and SPR analysis. HLA-G mediated signaling and competition was assessed using functional cell lines. Effect of iosH2 on activation of SHP1/2 was assessed using Western Blot. Functional assays including in vitro polarization and phagocytosis potential of primary macrophages was assessed by flow cytometry in the presence of iosH2 or isotype control. Effect of iosH2 on T cell activation was evaluated in co-cultures of cancer and T cells. Mouse models were used to assess in vivo activity.Results iosH2 binds to LILRB2 with high affinity and blocks the activation of HLA-G. In addition, iosH2 blocks receptor-mediated activation of SHP1/2. iosH2 promotes a shift from M2 to M1 macrophages with enhanced tumor cell phagocytosis in vitro. iosH2 enhances activation and killing potential of T cells in cancer cells and T cells co-culture assay. iosH2 exerts therapeutic efficacy in mouse transgenic (melanoma) and different syngeneic tumor models (e.g. pancreatic, colon and breast cancer) as monotherapy. Moreover, it acts synergistically in vivo with PD1 blocking antibodies achieving long-term tumor control. Ex vivo tumor sample analysis demonstrates a significant reduction of MDSC and Tregs and a shift towards an activated inflammatory M1 macrophage phenotype. Loss of MDSC functionality was paralleled by enhanced CD8+ T cell expansion and activity.Conclusions iosH2 binds to LILRB2 with high affinity, restores immune cell function in vitro and demonstrates anti-tumor activity in different in vivo mouse models. In addition, it acts synergistically in vivo with PD1. iosH2 is a first-in-class OC therapeutic with robust anti-tumor activity by promoting key components of the innate immune system. Clinical development is under way and phase I trial in preparation.

The role of dendritic cells in shaping the immune response

2004 ◽  
Vol 5 (2) ◽  
pp. 191-195 ◽  
Author(s):  
C. J. Howard ◽  
B. Charleston ◽  
S. A. Stephens ◽  
P. Sopp ◽  
J. C. Hope
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Immune System ◽  
Innate Immune System ◽  
Adaptive Response ◽  
Ex Vivo ◽  
T Cell Response ◽  
Innate Immune ◽  
Myeloid Dendritic Cells

AbstractDendritic cells are central to the initiation of primary immune responses. They are the only antigen-presenting cell capable of stimulating naive T cells, and hence they are pivotal in the generation of adaptive immunity. Dendritic cells also interact with and influence the response of cells of the innate immune system. The manner in which dendritic cells influence the responses in cells of both the innate and adaptive immune systems has consequences for the bias of the adaptive response that mediates immunity to infection after vaccination or infection. It also provides an opportunity to intervene and to influence the response, allowing ways of developing appropriate vaccination strategies. Mouse and human studies have identified myeloid, lymphoid and plasmacytoid dendritic cells. Studies in domesticated animals with agents of specific infectious diseases have confirmed the applicability of certain of the generic models developed from mice or from in vitro studies on human cells. In vivo and ex vivo studies in cattle have demonstrated the existence of a number of subpopulations of myeloid dendritic cells. These cells differ in their ability to stimulate T cells and in the cytokines that they produce, observations clearly having important implications for the bias of the T-cell response. Dendritic cells also interact with the innate immune system, inducing responses that potentially bias the subsequent adaptive response.

Sign in / Sign up

Export Citation Format

Share Document