scholarly journals Regulation of MHC-I and MHC-II by CIITA in transmissible cancers

2021 ◽  
Author(s):  
Chrissie E. B. Ong ◽  
Yuanyuan Cheng ◽  
Hannah Siddle ◽  
A. Bruce Lyons ◽  
Gregory M. Woods ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tasmanian Devil ◽  
Mhc I ◽  
Mhc Ii ◽  
Cell Immunity ◽  
Devil Facial Tumour Disease ◽  
Novel Strategy

MHC-I and MHC-II molecules are critical components of antigen presentation and T cell immunity to pathogens and cancer. The transmissible devil facial tumour (DFT) cells that cause Tasmanian devil facial tumour disease (DFTD) exploit MHC-I pathways to overcome immunological anti-tumour and allogeneic barriers. This exploitation underpins the ongoing transmission of DFT cells across the wild Tasmanian devil population. MHC-II expression is crucial for CD4+ T cell activation and is primarily confined to haematopoietic antigen presenting cells. We discovered that the MHC-II transactivator, CIITA, can induce MHC-II expression in non-haematopoietic cells. Transcriptomic analysis of DFT cell lines revealed that CIITA can upregulate several genes of the MHC-I and MHC-II pathways, resulting in protein expression of MHC-I and MHC-II complexes. The induced expression of MHC-II in transmissible cancers signifies that CIITA can function in non-haematopoietic cancer cells and offer a novel strategy to enhance tumour recognition via MHC-II-restricted tumour antigen presentation.

scholarly journals Astrocytes have the capacity to act as antigen-presenting cells in the Parkinson’s disease brain

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Jinar Rostami ◽  
Grammatiki Fotaki ◽  
Julien Sirois ◽  
Ropafadzo Mzezewa ◽  
Joakim Bergström ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antigen Presenting Cells ◽  
Human Microglia ◽  
Mhc Ii ◽  
Human Astrocytes ◽  
Antigen Presenting

Abstract Background Many lines of evidence suggest that accumulation of aggregated alpha-synuclein (αSYN) in the Parkinson’s disease (PD) brain causes infiltration of T cells. However, in which ways the stationary brain cells interact with the T cells remain elusive. Here, we identify astrocytes as potential antigen-presenting cells capable of activating T cells in the PD brain. Astrocytes are a major component of the nervous system, and accumulating data indicate that astrocytes can play a central role during PD progression. Methods To investigate the role of astrocytes in antigen presentation and T-cell activation in the PD brain, we analyzed post mortem brain tissue from PD patients and controls. Moreover, we studied the capacity of cultured human astrocytes and adult human microglia to act as professional antigen-presenting cells following exposure to preformed αSYN fibrils. Results Our analysis of post mortem brain tissue demonstrated that PD patients express high levels of MHC-II, which correlated with the load of pathological, phosphorylated αSYN. Interestingly, a very high proportion of the MHC-II co-localized with astrocytic markers. Importantly, we found both perivascular and infiltrated CD4+ T cells to be surrounded by MHC-II expressing astrocytes, confirming an astrocyte T cell cross-talk in the PD brain. Moreover, we showed that αSYN accumulation in cultured human astrocytes triggered surface expression of co-stimulatory molecules critical for T-cell activation, while cultured human microglia displayed very poor antigen presentation capacity. Notably, intercellular transfer of αSYN/MHC-II deposits occurred between astrocytes via tunneling nanotubes, indicating spreading of inflammation in addition to toxic protein aggregates. Conclusions In conclusion, our data from histology and cell culture studies suggest an important role for astrocytes in antigen presentation and T-cell activation in the PD brain, highlighting astrocytes as a promising therapeutic target in the context of chronic inflammation.

scholarly journals CD9 Regulates Major Histocompatibility Complex Class II Trafficking in Monocyte-Derived Dendritic Cells

2017 ◽  
Vol 37 (15) ◽  
Author(s):  
Vera Rocha-Perugini ◽  
Gloria Martínez del Hoyo ◽  
José María González-Granado ◽  
Marta Ramírez-Huesca ◽  
Virginia Zorita ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Complex Class ◽  
Gm Csf ◽  
Mhc Ii ◽  
Histocompatibility Complex

ABSTRACT Antigen presentation by dendritic cells (DCs) stimulates naive CD4+ T cells, triggering T cell activation and the adaptive arm of the immune response. Newly synthesized major histocompatibility complex class II (MHC-II) molecules accumulate at MHC-II-enriched endosomal compartments and are transported to the plasma membrane of DCs after binding to antigenic peptides to enable antigen presentation. In DCs, MHC-II molecules are included in tetraspanin-enriched microdomains (TEMs). However, the role of tetraspanin CD9 in these processes remains largely undefined. Here, we show that CD9 regulates the T cell-stimulatory capacity of granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent bone marrow-derived DCs (BMDCs), without affecting antigen presentation by fms-like tyrosine kinase 3 ligand (Flt3L)-dependent BMDCs. CD9 knockout (KO) GM-CSF-dependent BMDCs, which resemble monocyte-derived DCs (MoDCs), induce lower levels of T cell activation than wild-type DCs, and this effect is related to a reduction in MHC-II surface expression in CD9-deficient MoDCs. Importantly, MHC-II targeting to the plasma membrane is largely impaired in immature CD9 KO MoDCs, in which MHC-II remains arrested in acidic intracellular compartments enriched in LAMP-1 (lysosome-associated membrane protein 1), and MHC-II internalization is also blocked. Moreover, CD9 participates in MHC-II trafficking in mature MoDCs, regulating its endocytosis and recycling. Our results demonstrate that the tetraspanin CD9 specifically regulates antigenic presentation in MoDCs through the regulation of MHC-II intracellular trafficking.

Prevention of T cell activation by interference of internalized intravenous immunoglobulin (IVIg) with MHC II-dependent native antigen presentation

2011 ◽  
Vol 141 (3) ◽  
pp. 273-283 ◽  
Author(s):  
Éric Aubin ◽  
Dominic Paquin Proulx ◽  
Patrick Trépanier ◽  
Réal Lemieux ◽  
Renée Bazin
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
Intravenous Immunoglobulin ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mhc Ii ◽  
Native Antigen

Abstract P148: Sex-dependent Colonic Immune Responses In Salt-sensitive Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Xue Mei ◽  
Saroj CHAKRABORTY ◽  
Xi Cheng ◽  
Tao Yang ◽  
Bina Joe
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
High Salt ◽  
B Cell Activation ◽  
Mhc I ◽  
Male And Female ◽  
Mhc Ii ◽  
Low Salt ◽  
Salt Sensitive Hypertension

Introduction: Hypertension affects almost half of the adults in the US. Overactivation of immune system results in pathogenesis of hypertension. Given that sex differences are reported in salt-sensitive hypertension and that the gut is an important organ at the interface between gut microbiota and the host, we hypothesized that differential colonic immunity exists between male and female rats on high and low salt diets. Methods: Total RNA was isolated from the colons of male and female Dahl Salt-Sensitive (S) rats fed with either high-salt (2% NaCl) or low-salt (0.3% NaCl) diet at 9-10 weeks old (n=3/sex/diet) and subjected to transcriptome followed by pathway analyses to detect differentially enriched transcripts and biological processes (FDR<0.05). The transcripts overexpressed in the sex-matched S rats on high salt diets were defined as hypertension-associated genes. Among them, the transcripts upregulated in both sexes were inferred as sex-independent, while those upregulated exclusively in either sex were considered as sex-dependent. Results: Upregulation of colonic immunity was evident through the transcriptomic signatures of both sexes with hypertension. Among the upregulated 38 male sex-dependent transcripts, 20 were related to T cell activation including co-receptor Cd4 , co-stimulators Cd80 and Cd86 , and Th1 and Treg cells-related receptors and cytokines Tgfbr2 , Il1r1 , Il18r1 and Lif , whereas 17 out of 27 upregulated female sex-dependent transcripts were related to T cell activation including co-receptor Cd8 , co-stimulators Cd40 , Icoslg , Cd27 , and Tnfsf9 , and Th2 and Th17-related cytokines Tgfb1 , Tgfb3 , Il1b , Il23a and Gata3 . In addition, antigen presenting cells were observed with upregulated MHC II in males, whereas upregulated both MHC I and II in females with hypertension. Further, 12 out of 20 sex-independent transcripts were suggestive of B cell activation. Conclusion: Marked sex differences were noted in the levels of colonic immune function- related transcripts of S rats on high salt diet. In the colonic T cell activation related transcripts, Cd4 and MHC II were predominant in males, while Cd8 and both MHC I and II were more prevalent in females. Additionally, colonic B cell activation was relatively less dependent on sex.

scholarly journals Hrd1-mediated BLIMP-1 ubiquitination promotes dendritic cell MHCII expression for CD4 T cell priming during inflammation

2014 ◽  
Vol 211 (12) ◽  
pp. 2467-2479 ◽  
Author(s):  
Heeyoung Yang ◽  
Quan Qiu ◽  
Beixue Gao ◽  
Sinyi Kong ◽  
Zhenghong Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
B Lymphocyte ◽  
Cd4 T Cell ◽  
Autoimmune Encephalomyelitis ◽  
Mhc I ◽  
Mhc Ii ◽  
Maturation Protein

The ubiquitin pathway plays critical roles in antigen presentation. However, the ubiquitin ligases that regulate MHC gene transcription remain unidentified. We showed that the ubiquitin ligase Hrd1, expression of which is induced by Toll-like receptor (TLR) stimulation, is required for MHC-II but not MHC-I transcription in dendritic cells (DCs). Targeted Hrd1 gene deletion in DCs diminished MHC-II expression. As a consequence, Hrd1-null DCs failed to prime CD4+ T cells without affecting the activation of CD8+ T cells. Hrd1 catalyzed ubiquitination and degradation of the transcriptional suppressor B lymphocyte–induced maturation protein 1 (BLIMP1) to promote MHC-II expression. Genetic suppression of Hrd1 function in DCs protected mice from myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis (EAE). We identified Hrd1-mediated BLIMP1 ubiquitination as a previously unknown mechanism in programming DC for CD4+ T cell activation during inflammation.

scholarly journals Dendritic cell and antigen dispersal landscapes regulate T cell immunity

2017 ◽  
Vol 214 (10) ◽  
pp. 3105-3122 ◽  
Author(s):  
Michael Y. Gerner ◽  
Kerry A. Casey ◽  
Wolfgang Kastenmuller ◽  
Ronald N. Germain
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Quantitative Imaging ◽  
Clonal Diversity ◽  
T Cell Immunity ◽  
Antigen Delivery ◽  
Mhc I ◽  
Cell Immunity

Dendritic cell (DC) subsets with biased capacity for CD4+ and CD8+ T cell activation are asymmetrically distributed in lymph nodes (LNs), but how this affects adaptive responses has not been extensively studied. Here we used quantitative imaging to examine the relationships among antigen dispersal, DC positioning, and T cell activation after protein immunization. Antigens rapidly drained into LNs and formed gradients extending from the lymphatic sinuses, with reduced abundance in the deep LN paracortex. Differential localization of DCs specialized for major histocompatibility complex I (MHC I) and MHC II presentation resulted in preferential activation of CD8+ and CD4+ T cells within distinct LN regions. Because MHC I–specialized DCs are positioned in regions with limited antigen delivery, modest reductions in antigen dose led to a substantially greater decline in CD8+ compared with CD4+ T cell activation, expansion, and clonal diversity. Thus, the collective action of antigen dispersal and DC positioning regulates the extent and quality of T cell immunity, with important implications for vaccine design.

scholarly journals High MHC-II expression in Epstein–Barr virus-associated gastric cancers suggests that tumor cells serve an important role in antigen presentation

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Farhad Ghasemi ◽  
Tanner M. Tessier ◽  
Steven F. Gameiro ◽  
Allison H. Maciver ◽  
Matthew J. Cecchini ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Gastric Cancers ◽  
Normal Tissues ◽  
Barr Virus ◽  
Mhc Ii ◽  
Inflammatory Conditions ◽  
The Impact

Abstract EBV-associated gastric adenocarcinomas (EBVaGCs) often exhibit better clinical outcomes than EBV negative gastric cancers (GCs), which could be related to their consistent expression of foreign viral antigens. Antigen-presenting cells (APCs) present peptide antigens in the context of the class-II major histocompatibility complex (MHC-II). During inflammatory conditions, epithelial cells express MHC-II and function as accessory APCs. Utilizing RNA-seq data from nearly 400 GC patients, we determined the impact of EBV-status on expression of MHC-II components, genes involved in their regulation, and T-cell co-stimulation. Virtually all MHC-II genes were significantly upregulated in EBVaGCs compared to normal tissues, or other GC subtypes. Genes involved in antigen presentation were also significantly upregulated in EBVaGCs, as were the key MHC-II transcriptional regulators CIITA and RFX5. This was unexpected as the EBV encoded BZLF1 protein can repress CIITA transcription and is expressed in many EBVaGCs. Furthermore, MHC-II upregulation was strongly correlated with elevated intratumoral levels of interferon-gamma. In addition, expression of co-stimulatory molecules involved in T-cell activation and survival was also significantly increased in EBVaGCs. Thus, gastric adenocarcinoma cells may functionally contribute to the highly immunogenic tumor microenvironment observed in EBVaGCs via a previously unappreciated role in interferon-induced antigen presentation.

scholarly journals Distinct editing functions of natural HLA-DM allotypes impact antigen presentation and CD4+ T cell activation

2018 ◽  
Vol 17 (2) ◽  
pp. 133-142 ◽  
Author(s):  
Miguel Álvaro-Benito ◽  
Eliot Morrison ◽  
Friederike Ebner ◽  
Esam T. Abualrous ◽  
Marie Urbicht ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 T Cell

scholarly journals Isolevuglandin-Modified Cardiac Proteins Drive CD4+ T Cell Activation in the Heart and Promote Cardiac Dysfunction

Circulation ◽  
2021 ◽  
Author(s):  
Njabulo Ngwenyama ◽  
Annet Kirabo ◽  
Mark Aronovitz ◽  
Francisco Velázquez ◽  
Francisco Carrillo-Salinas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cardiac Dysfunction ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Myocardial Oxidative Stress

Background: Despite the well-established association between T cell-mediated inflammation and non-ischemic heart failure (HF), the specific mechanisms triggering T cell activation during the progression of HF and the antigens involved are poorly understood. We hypothesized that myocardial oxidative stress induces the formation of isolevuglandin (IsoLG)-modified proteins that function as cardiac neoantigens to elicit CD4+ T cell receptor (TCR) activation and promote HF. Methods: We used transverse aortic constriction (TAC) in mice to trigger myocardial oxidative stress and T cell infiltration. We profiled the TCR repertoire by mRNA sequencing of intramyocardial activated CD4+ T cells in Nur77 GFP reporter mice, which transiently express GFP upon TCR engagement. We assessed the role of antigen presentation and TCR specificity in the development of cardiac dysfunction using antigen presentation-deficient MhcII -/- mice, and TCR transgenic OTII mice that lack specificity for endogenous antigens. We detected IsoLG-protein adducts in failing human hearts. We also evaluated the role of reactive oxygen species (ROS) and IsoLGs in eliciting T cell immune responses in vivo by treating mice with the antioxidant TEMPOL, and the IsoLG scavenger 2-hydroxybenzylamine (2-HOBA) during TAC, and ex-vivo in mechanistic studies of CD4+ T cell proliferation in response to IsoLG-modified cardiac proteins. Results: We discovered that TCR antigen recognition increases in the left ventricle (LV) as cardiac dysfunction progresses, and identified a limited repertoire of activated CD4+ T cell clonotypes in the LV. Antigen presentation of endogenous antigens was required to develop cardiac dysfunction since MhcII -/- mice reconstituted with CD4+ T cells, and OTII mice immunized with their cognate antigen were protected from TAC-induced cardiac dysfunction despite the presence of LV-infiltrated CD4+ T cells. Scavenging IsoLGs with 2-HOBA reduced TCR activation and prevented cardiac dysfunction. Mechanistically, cardiac pressure overload resulted in ROS dependent dendritic cell accumulation of IsoLG-protein adducts which induced robust CD4+ T cell proliferation. Conclusions: Collectively, our study demonstrates an important role of ROS-induced formation of IsoLG-modified cardiac neoantigens that lead to TCR-dependent CD4+ T cell activation within the heart.

scholarly journals Brucella Peptide Cross-Reactive MHC I Presentation Activates SIINFEKL-Specific TCR Expressing T Cells

2018 ◽  
Author(s):  
Jerome S. Harms ◽  
Mike Khan ◽  
Cherisse Hall ◽  
Gary A. Splitter ◽  
E. Jane Homan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Pathogenic Bacteria ◽  
Cell Activation ◽  
Immune Surveillance ◽  
Cross Reactivity ◽  
Near Neighbor ◽  
Target Cells ◽  
Mhc I

ABSTRACTBrucella spp are intracellular pathogenic bacteria remarkable in their ability to escape immune surveillance and therefore inflict a state of chronic disease within the host. To enable further immune response studies, Brucella were engineered to express the well characterized chicken ovalbumin (OVA). Surprisingly, we found that CD8 T cells bearing T cell receptors (TCR) nominally specific for the OVA peptide SIINFEKL (OT-1) reacted to parental Brucella-infected targets as well as OVA-expressing Brucella variants in cytotoxicity assays. Furthermore, splenocytes from Brucella immunized mice produced IFN-γ and exhibited cytotoxicity in response to SIINFEKL-pulsed target cells. To determine if the SIINFEKL-reactive OT-1 TCR could be cross-reacting to Brucella peptides, we searched the Brucella proteome using an algorithm to generate a list of near-neighbor nonamer peptides that would bind to H2Kb. Selecting five Brucella peptide candidates, along with controls, we verified that several of these peptides mimicked SIINFEKL resulting in T cell activation through the “SIINFEKL-specific” TCR. Activation was dependent on peptide concentration as well as sequence. Our results underscore the complexity and ubiquity of cross-reactivity in T cell recognition. This cross-reactivity may enable microbes such as Brucella to escape immune surveillance by presenting peptides similar to the host, and may also lead to the activation of autoreactive T cells.

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