scholarly journals BRG1 Mediates Nephronectin Activation in Hepatocytes to Promote T Lymphocyte Infiltration in ConA-Induced Hepatitis

2021 ◽  
Vol 8 ◽  
Author(s):  
Wenxuan Hong ◽  
Ming Kong ◽  
Mengwen Qi ◽  
Hui Bai ◽  
Zhiwen Fan ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Hepatitis ◽  
T Lymphocyte ◽  
Lymphocyte Migration ◽  
Cell Homing ◽  
Biopsy Specimens ◽  
T Cell Homing ◽  
Lectin Family ◽  
Massive Accumulation

Fulminant hepatitis (FH) is a major cause of acute liver failure. Concanavalin A (ConA) belongs to the lectin family and is frequently used as an inducer of FH in animal models. ConA induced FH is characterized by massive accumulation of T lymphocytes in the liver. A host of chemoattractive substances are known to promote T cell homing to the liver during acute hepatitis. Here we investigated the involvement of Brahma-related gene 1 (BRG1), a chromatin remodeling protein, in FH. BRG1-flox mice were crossed to Alb-Cre mice to generate hepatocyte conditional BRG1 knockout (LKO) mice. The mice were peritoneally injected with a single dose of ConA to induce FH. BRG1 deficiency mitigated ConA-induced FH in mice. Consistently, there were fewer T lymphocyte infiltrates in the LKO livers compared to the wild type (WT) livers paralleling downregulation of T cell specific cytokines. Further analysis revealed that BRG1 deficiency repressed the expression of several chemokines critical for T cell homing including nephronectin (Npnt). BRG1 knockdown blocked the induction of Npnt in hepatocytes and attenuated T lymphocyte migration in vitro, which was reversed by the addition of recombinant nephronectin. Mechanistically, BRG1 interacted with β-catenin to directly bind to the Npnt promoter and activate Npnt transcription. Importantly, a positive correlation between infiltration of CD3+ T lymphocyes and nephronectin expression was detected in human acute hepatitis biopsy specimens. In conclusion, our data identify a novel role for BRG1 as a promoter of T lymphocyte trafficking by activating Npnt transcription in hepatocytes. Targeting the BRG1-Npnt axis may yield novel therapeutic solutions for FH.

Abstract 154: Atherosclerosis-specific CD4 T Cells Use the Chemokine CCL5 and Its Receptor CCR5 to Home to Mature Atherosclerotic Lesions in Mice

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Jie Li ◽  
Klaus Ley
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Transcriptomic Analysis ◽  
Cell Phenotype ◽  
Color Flow ◽  
Cell Homing ◽  
T Cell Homing

Introduction: T cell adaptive immunity is involved in the pathogenesis of atherosclerosis, but the phenotype of T cell subset and chemokine receptor that regulates effector T cell trafficking to atherosclerotic aortas is unknown. By multi-color flow cytometry, we discovered that >40% of T cells in the atherosclerotic aortas express CCR5. We hypothesize that CCR5 plays an important role in T cell recruitment to atherosclerotic aortas and CCR5+ T cells play an important roll in the pathogenesis of atherosclerosis. Methods: T cell phenotype in the aorta of Apoe -/- mice on western diet 3-5 months was analyzed by multi-color flow cytometry. T cell homing assay were done in vitro by incubating 400,000 T eff from CD45.1Apoe -/- mice with explanted Apoe -/- aortas 12 to 18 hrs with media alone, CCL5 neutralizing antibody (0.5 ug/ml) or PTX (300ng/ml), and in vivo by adoptively transferring splenocytes from Apoe -/- Ccr5 -/- and dsRedApoe -/- mice at 1:1 ratio into CD45.1Apoe -/- recipients. 24 hours later, recipient aortas were digested and analyzed by flow cytometry. To visualize T cell proximity to APCs in the aorta by 2 photon imaging, T eff from Apoe -/- mice were labeled with SNARF before incubation with explanted aortas from CD11c-YFP+Apoe -/- mice in the above 3 conditions. In vitro T cell suppression assay was done by incubating 10 4 CD4+CD25- T cells with α-CD3 mAb and 5x10 4 irradiated splenic APCs and decreasing amount of Treg or CCR5Teff. Transcriptomic analysis is done following SMARTseq II prortocol from Illumina. Results: 43±6% of αβ T cells in the atherosclerotic aortas express CCR5, significantly higher than that in aortas of wild-type C57BL/6 mice (10±7%) or Apoe -/- mice on normal diet (7±6%). CCR5 and its ligand CCL5 play the major role in regulating T cell homing to atherosclerotic aortas in vitro and in vivo . Interestingly, at late stage of disease, the CCR5+ T cells in the atherosclerotic plaques are all FoxP3 + IFN-γ + T-bet + CD25 - CD44 hi CD62L lo (CCR5Teff) and do not suppress T cell proliferation. CCR5Teffs are only found in the aorta and para-aortic lymph nodes of Apoe -/- mice but not in the spleen or other organs. Transcriptomic analysis shows that CCR5Teff is more similar to Teff rather than Tregs.

scholarly journals Integrin Function in T-Cell Homing to Lymphoid and Nonlymphoid Sites: Getting There and Staying There

2009 ◽  
Vol 29 (2) ◽  
pp. 87-109 ◽  
Author(s):  
Christopher C. DeNucci ◽  
Jason S. Mitchell ◽  
Yoji Shimizu
Keyword(s):  
T Cell ◽  
Cell Homing ◽  
T Cell Homing

scholarly journals Human bone marrow and peripheral blood T lymphocyte depletion: efficacy and effects of both T cells and monocytes on growth of hematopoietic progenitors

Blood ◽  
1985 ◽  
Vol 65 (3) ◽  
pp. 663-679
Author(s):  
L Levitt ◽  
TJ Kipps ◽  
EG Engleman ◽  
PL Greenberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Peripheral Blood ◽  
Cell Depletion ◽  
Target Cells ◽  
Facs Analysis ◽  
Hematopoietic Progenitors ◽  
T Cell Depletion

The efficacy of four separate methods of human bone marrow T lymphocyte depletion was assessed, and the effect of T cells and monocytes on in vitro growth of marrow (CFU-GEMM, BFU-E, and CFU-GM) and peripheral blood (BFU-E) hematopoietic progenitors was determined. Extent of T cell depletion was assessed by multiparameter fluorescent cell sorter (FACS) analysis and by functional studies. Cells staining positively by FACS analysis for one or more of three separate fluorescent pan-T cell monoclonal antibodies (MCAbs) comprised 8.4% to 9.5% of control marrow mononuclear cells (MNCs). T cells constituted 3.2% to 5.1% of marrow following single, sequential, or combination treatment with two different pan-T cell MCAbs (Leu 1 and TM1) plus complement, 1.5% to 2.2% of marrow following solid-phase immunoabsorption (“panning”), 0.2% of marrow after sheep cell rosetting, and only 0.05% of marrow after FACS selective cell sorting and gated separation. T cells made up 59% to 73% of control peripheral blood MNCs and 0.8% to 2.8% of peripheral MNCs following sheep cell rosetting plus treatment with Leu 1 MCAb and complement. Mitogen (PHA, Con A) and allogeneic MLC-induced blastogenic responses (stimulation indices, experimental/control or E/C) revealed a concordant decrement in marrow T cell function after MCAb plus complement (E/C of 3.9 to 9.0), after panning (E/C of 1.6 to 3.5) and after sheep cell rosetting (E/C of 0.7 to 1.3), compared with control marrow (E/C of 5.3 to 15.7). After T cell depletion, marrow BFU-E growth was 95% to 120% of control, CFU-GM growth was 90% to 108% of control, and CFU-GEMM growth was 89% to 111% of control. Marrow T cell and/or monocyte depletion did not alter erythropoietin-dependent BFU-E growth in the absence of Mo-conditioned medium (81% to 95% of control), and the addition of as many as 50 to 100 X 10(3) purified marrow monocytes or T cells to 10(5) autologous nonadherent T cell-depleted marrow target cells had a negligible (P greater than .1) effect on marrow BFU-E growth in vitro. Peripheral blood (PB) BFU-E/10(5) T- depleted target cells were 106% +/- 19% of expected; PB BFU-E growth was significantly diminished after monocyte depletion alone (7% +/- 6% of expected) or after monocyte plus T cell depletion (8% +/- 4% of expected).(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Functional Reprogramming of the Primary Immune Response by T Cell Receptor Antagonism

2004 ◽  
Vol 200 (11) ◽  
pp. 1371-1382 ◽  
Author(s):  
Dipica Haribhai ◽  
Brandon Edwards ◽  
Mary L. Williams ◽  
Calvin B. Williams
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Fate ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Effector Function ◽  
Primary Immune Response ◽  
Cell Homing ◽  
T Cell Homing ◽  
Cell Receptor Antagonism

The T cell receptor must translate modest, quantitative differences in ligand binding kinetics into the qualitatively distinct signals used to determine cell fate. Here, we use mice that express an endogenous T cell receptor (TCR) antagonist and an adoptive transfer system to examine the influence of TCR signal quality on the development of effector function. We show that activation of antigen-specific T cells in the presence of an antagonist results in a functional reprogramming of the primary immune response, marked by altered T cell homing, a failure to develop effector function, and ultimately clonal elimination by apoptosis. Importantly, antagonism does not block cell division, implying that the signals promoting clonal expansion and effector differentiation are distinct.

scholarly journals Enhanced immune activity of cytotoxic T-lymphocyte epitope analogs derived from positional scanning synthetic combinatorial libraries

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1776-1786 ◽  
Author(s):  
Corinna La Rosa ◽  
Radhika Krishnan ◽  
Susan Markel ◽  
Jonathan P. Schneck ◽  
Richard Houghten ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Combinatorial Libraries ◽  
Peptide Sequence ◽  
Ctl Epitopes ◽  
Ctl Epitope ◽  
Positional Scanning ◽  
Synthetic Combinatorial Libraries

The pp65495-503 cytotoxic T-lymphocyte (CTL) epitope from cytomegalovirus (CMV) is universally recognized among CMV+ individuals who express an allele of the human leukocyte antigen A (HLA-A*0201). The relative binding affinity of the epitope to HLA-A*0201 is moderate, and its increased activity might prove beneficial in its use as a CTL epitope vaccine. A new approach to enhance the activity of T-cell epitopes is the use of positional scanning synthetic combinatorial libraries (PS-SCLs). Using a nonamer PS-SCL, the pp65495-503 epitope was modified after screening a CMV-specific T-cell clone (TCC) (3-3F4) from which the native peptide sequence was derived. Two peptides with amino acid substitutions at P1, P3, P7, and P8 are between 103 and 104 more active than the native epitope. Although the native CTL epitope terminates as a free acid, both tetrasubstituted peptides only function as CTL epitopes when the carboxyl terminus is amidated. Selective substitution of the native sequence based on PS-SCL screening results identified 3 amidated monosubstituted and disubstituted peptides that are better recognized than the native epitope by TCCs from a cohort expressing HLA-A*0201. In vitro stimulation of peripheral blood mononuclear cells with each of the peptide epitope analogs stimulated memory CTLs, which recognized CMV-infected targets among a high percentage of CMV+ individuals. Binding studies of peptide analogs with HLA-Ig (immunoglobulin) dimers and 2 different TCCs correlated with in vitro lysis results. These data suggest that increasing the activity of CTL epitopes while maintaining broad recognition is possible, which holds promise for vaccine development in infectious disease and cancer.

scholarly journals Gamma Interferon Is Required for Chlamydia Clearance but Is Dispensable for T Cell Homing to the Genital Tract

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Jennifer D. Helble ◽  
Rodrigo J. Gonzalez ◽  
Ulrich H. von Andrian ◽  
Michael N. Starnbach
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Chlamydia Trachomatis ◽  
Genital Tract ◽  
Gamma Interferon ◽  
Cell Homing ◽  
Content Type ◽  
T Cell Homing ◽  
Ifn Γ

ABSTRACT While there is no effective vaccine against Chlamydia trachomatis infection, previous work has demonstrated the importance of C. trachomatis-specific CD4+ T cells (NR1 T cells) in pathogen clearance. Specifically, NR1 T cells have been shown to be protective in mice, and this protection depends on the host’s ability to sense the cytokine gamma interferon (IFN-γ). However, it is unclear what role NR1 production or sensing of IFN-γ plays in T cell homing to the genital tract or T cell-mediated protection against C. trachomatis. Using two-photon microscopy and flow cytometry, we found that naive wild-type (WT), IFN-γ−/−, and IFN-γR−/− NR1 T cells specifically home to sections in the genital tract that contain C. trachomatis. We also determined that protection against infection requires production of IFN-γ from either NR1 T cells or endogenous cells, further highlighting the importance of IFN-γ in clearing C. trachomatis infection. IMPORTANCE Chlamydia trachomatis is an important mucosal pathogen that is the leading cause of sexually transmitted bacterial infections in the United States. Despite this, there is no vaccine currently available. In order to develop such a vaccine, it is necessary to understand the components of the immune response that can lead to protection against this pathogen. It is well known that antigen-specific CD4+ T cells are critical for Chlamydia clearance, but the contexts in which they are protective or not protective are unknown. Here, we aimed to characterize the importance of gamma interferon production and sensing by T cells and the effects on the immune response to C. trachomatis. Our work here helps to define the contexts in which antigen-specific T cells can be protective, which is critical to our ability to design an effective and protective vaccine against C. trachomatis.

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