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Allergy Jan 2024Circulating skin-homing cutaneous lymphocyte-associated antigen (CLA) T cells constitute a small subset of human memory T cells involved in several aspects of atopic... (Review)
Review
Circulating skin-homing cutaneous lymphocyte-associated antigen (CLA) T cells constitute a small subset of human memory T cells involved in several aspects of atopic dermatitis: Staphylococcus aureus related mechanisms, the abnormal Th2 immune response, biomarkers, clinical aspects of the patients, pruritus, and the mechanism of action of targeted therapies. Superantigens, IL-13, IL-31, pruritus, CCL17 and early effects on dupilumab-treated patients have in common that they are associated with the CLA T cell mechanisms in atopic dermatitis patients. The function of CLA T cells corresponds with the role of T cells belonging to the skin-associated lymphoid tissue and could be a reason why they reflect different mechanisms of atopic dermatitis and many other T cell mediated skin diseases. The goal of this review is to gather all this translational information of atopic dermatitis pathology.
Topics: Humans; Dermatitis, Atopic; Memory T Cells; T-Lymphocyte Subsets; Antigens, Differentiation, T-Lymphocyte; Membrane Glycoproteins; Receptors, Lymphocyte Homing; Skin; Pruritus; Antigens, Neoplasm
PubMed: 37439317
DOI: 10.1111/all.15816 -
International Journal of Molecular... Dec 2023Cancer management still requires more potent and safer treatments, of which immunomodulatory receptors on the lymphocyte surface have started to show promise in new... (Review)
Review
Cancer management still requires more potent and safer treatments, of which immunomodulatory receptors on the lymphocyte surface have started to show promise in new cancer immunotherapies (e.g., CTLA-4 and PD-1). CD6 is a signal-transducing transmembrane receptor, mainly expressed by all T cells and some B and NK cell subsets, whose endogenous ligands (CD166/ALCAM, CD318/CDCP-1, Galectins 1 and 3) are overexpressed by malignant cells of different lineages. This places CD6 as a potential target for novel therapies against haematological and non-haematological malignancies. Recent experimental evidence for the role of CD6 in cancer immunotherapies is summarised in this review, dealing with diverse and innovative strategies from the classical use of monoclonal antibodies to soluble recombinant decoys or the adoptive transfer of immune cells engineered with chimeric antigen receptors.
Topics: Activated-Leukocyte Cell Adhesion Molecule; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Immunotherapy; Neoplasms; T-Lymphocytes
PubMed: 38139340
DOI: 10.3390/ijms242417510 -
Cancer Research Dec 2023Identifying novel cell surface receptors that regulate leukemia cell differentiation and can be targeted to inhibit cellular proliferation is crucial to improve current...
UNLABELLED
Identifying novel cell surface receptors that regulate leukemia cell differentiation and can be targeted to inhibit cellular proliferation is crucial to improve current treatment modalities in acute myeloid leukemia (AML), especially for relapsed or chemotherapy-refractory leukemia. Leukocyte immunoglobulin-like receptor type B (LILRB) is an immunomodulatory receptor originally found to be expressed in myeloid cells. In this study, we found that LILRB receptors can be induced under inflammatory stimuli and chemotherapy treatment conditions. Blockade of LILRB3 inhibited leukemia cell proliferation and leukemia progression. In addition, treatment with LILRB3 blocking antibodies upregulated myeloid lineage differentiation transcription factors, including PU.1, C/EBP family, and IRF, whereas phosphorylation of proliferation regulators, for example, AKT, cyclin D1, and retinoblastoma protein, was decreased. Conversely, transcriptomic analysis showed LILRB3 activation by agonist antibodies may enhance leukemia survival through upregulation of cholesterol metabolism, which has been shown to promote leukemia cell survival. Moreover, LILRB3-targeted CAR T cells exhibited potent antitumor effects both in vitro and in vivo. Taken together, our results suggest that LILRB3 is a potentially potent target for multiple treatment modalities in AML.
SIGNIFICANCE
LILRB3 regulates differentiation and proliferation in acute myeloid leukemia and can be targeted with monoclonal antibodies and CAR T cells to suppress leukemia growth.
Topics: Humans; Immunotherapy, Adoptive; T-Lymphocytes; Leukemia, Myeloid, Acute; Receptors, Cell Surface; Myeloid Cells; Receptors, Immunologic; Antigens, CD
PubMed: 38098451
DOI: 10.1158/0008-5472.CAN-22-2483 -
Transfusion and Apheresis Science :... Oct 2023Significant advances in procedural information displayed by current apheresis machines have been made, but analyses of cell collection efficiency (CE) still rely on...
Significant advances in procedural information displayed by current apheresis machines have been made, but analyses of cell collection efficiency (CE) still rely on calculations done by apheresis professionals. Accordingly, understanding CE equations can support the optimization of apheresis techniques and identification of incidents that could impact the procedure's effectiveness. This report summarizes classical and novel CE analyses applied to apheresis exemplified by an actual case of hematopoietic progenitor cell collection. In addition to the apheresis yield and most common CE and CE formulas, we present the instantaneous and corrected CE, fold enrichment, collection throughput, collection rate and its variants, average inlet rate, classical and adjusted captured cells, recruitment pool, recruitment factor, recruitment coefficient, blood component loss, predictive apheresis yield, and performance ratio calculations. Moreover, the mathematical relationship between these CE equations is also shown, which can be helpful in many apheresis procedures.
Topics: Humans; Leukapheresis; Blood Component Removal; Hematopoietic Stem Cells; Antigens, CD34
PubMed: 37438245
DOI: 10.1016/j.transci.2023.103758 -
Journal of Reproductive Immunology Sep 2023Preeclampsia is more common in nulliparous women, their first pregnancies with a new partner in multiparous women, pregnant women with short duration of cohabitation,... (Review)
Review
Preeclampsia is more common in nulliparous women, their first pregnancies with a new partner in multiparous women, pregnant women with short duration of cohabitation, and in pregnancies with donor eggs, where the fetus is completely foreign to the mother. The epidemiological study findings strongly suggest that inadequate induction of tolerance to paternal/fetal antigens is involved in the pathogenesis of preeclampsia. This review proposes that preeclampsia may be caused by a reduction in paternal/fetal antigen-specific regulatory T (Treg) cells and decreased PD-1 expression on clonally expanded CD8 effector memory T (T) cells, resulting in a breakdown of mother-to-fetus tolerance. The immune environment of preeclampsia is clearly different from that of recurrent pregnancy loss (RPL). In preeclampsia, cloned Treg cells decreases, and PD-1 expression on cloned CD8T decreased. In RPL, the total number of Treg cells decreased, and the total number of clonally expanded CD8T cells increases. In addition to these changes, increased differentiation of Th17 cells has also been observed in preeclampsia. This change is caused by soluble endoglin, that is increased in preeclampsia, neutralizing TGFβ. These immunological changes make the fetus more susceptible to attacks from maternal T cells.
Topics: Female; Humans; Pregnancy; Pre-Eclampsia; Programmed Cell Death 1 Receptor; T-Lymphocytes, Regulatory; Antigens; Immune Tolerance; Abortion, Habitual
PubMed: 37573650
DOI: 10.1016/j.jri.2023.104125 -
Science Immunology Sep 2024TCRαβCD8αα intraepithelial lymphocytes (CD8αα αβ IELs) are a specialized subset of T cells in the gut epithelium that develop from thymic agonist selected IEL...
TCRαβCD8αα intraepithelial lymphocytes (CD8αα αβ IELs) are a specialized subset of T cells in the gut epithelium that develop from thymic agonist selected IEL precursors (IELps). The molecular mechanisms underlying the selection and differentiation of this T cell type in the thymus are largely unknown. Here, we found that deficiency in αβ T cells resulted in the near absence of CD8αα αβ IELs. BCL6 was expressed by approximately 50% of CD8αα αβ IELs and by the majority of thymic PD1 IELps after agonist selection. deficiency blocked early IELp generation in the thymus, and its expression in IELps was induced by thymic TCR signaling in an ERK-dependent manner. As a result of deficiency, the precursors of IELps among CD4CD8 double-positive thymocytes exhibited increased apoptosis during agonist selection and impaired IELp differentiation and maturation. Together, our results elucidate BCL6 as a crucial transcription factor during the thymic development of CD8αα αβ IELs.
Topics: Animals; Mice; CD8 Antigens; CD8-Positive T-Lymphocytes; Intestinal Mucosa; Intraepithelial Lymphocytes; Mice, Knockout; Receptors, Antigen, T-Cell, alpha-beta; Proto-Oncogene Proteins c-bcl-6
PubMed: 38335269
DOI: 10.1126/sciimmunol.adk4348 -
International Journal of Molecular... Aug 2023CD155, also known as the poliovirus receptor, is an adhesion molecule often overexpressed in tumors of different origins where it promotes cell migration and... (Review)
Review
CD155, also known as the poliovirus receptor, is an adhesion molecule often overexpressed in tumors of different origins where it promotes cell migration and proliferation. In addition to this pro-tumorigenic function, CD155 plays an immunomodulatory role during tumor progression since it is a ligand for both the activating receptor DNAM-1 and the inhibitory receptor TIGIT, expressed on cytotoxic innate and adaptative lymphocytes. DNAM-1 is a well-recognized receptor involved in anti-tumor immune surveillance. However, in advanced tumor stages, TIGIT is up-regulated and acts as an immune checkpoint receptor, counterbalancing DNAM-1-mediated cancer cell clearance. Pre-clinical studies have proposed the direct targeting of CD155 on tumor cells as well as the enhancement of DNAM-1-mediated anti-tumor functions as promising therapeutic approaches. Moreover, immunotherapeutic use of anti-TIGIT blocking antibody alone or in combined therapy has already been included in clinical trials. The aim of this review is to summarize all these potential therapies, highlighting the still controversial role of CD155 during tumor progression.
Topics: Humans; Carcinogenesis; Cell Movement; Receptors, Virus; Receptors, Immunologic; Antigens, Differentiation, T-Lymphocyte; Animals
PubMed: 37629138
DOI: 10.3390/ijms241612958 -
Nature Communications Aug 2023The rapid spread of monkeypox in multiple countries has resulted in a global public health threat and has caused international concerns since May 2022. Poxvirus encoded...
The rapid spread of monkeypox in multiple countries has resulted in a global public health threat and has caused international concerns since May 2022. Poxvirus encoded M2 protein is a member of the poxvirus immune evasion family and plays roles in host immunomodulation via the regulation of innate immune response mediated by the NF-κB pathway and adaptive immune response mediated by B7 ligands. However, the interaction of monkeypox virus (MPXV) M2 with B7 ligands and structural insight into poxviral M2 function have remained elusive. Here we reveal that MPXV M2, co-existing as a hexamer and a heptamer, recognizes human B7.1 and B7.2 (hB7.1/2) with high avidities. The binding of oligomeric MPXV M2 interrupts the interactions of hB7.1/2 with CD28 and CTLA4 and subverts T cell activation mediated by B7.1/2 costimulatory signals. Cryo-EM structures of M2 in complex with hB7.1/2 show that M2 binds to the shallow concave face of hB7.1/2 and displays sterically competition with CD28 and CTLA4 for the binding to hB7.1/2. Our findings provide structural mechanisms of poxviral M2 function and immune evasion deployed by poxviruses.
Topics: Humans; Mpox (monkeypox); Monkeypox virus; CTLA-4 Antigen; CD28 Antigens; Ligands; Poxviridae; T-Lymphocytes
PubMed: 37626059
DOI: 10.1038/s41467-023-40748-2 -
Journal of Cellular and Molecular... Dec 2023Gingival mesenchymal stem cells (GMSCs) are newly developed seed cells for tissue engineering owing to their easy isolation, abundance and high growth rates. Thy-1 is an...
Gingival mesenchymal stem cells (GMSCs) are newly developed seed cells for tissue engineering owing to their easy isolation, abundance and high growth rates. Thy-1 is an important regulatory molecule in the differentiation of mesenchymal stem cells (MSCs). In this study, we investigated the function of Thy-1 in the osteogenic differentiation of GMSCs by reducing the expression of Thy-1 using a lentivirus. The results demonstrated that Thy-1 knockdown promoted the osteogenic differentiation of GMSCs in vitro. Validation by RNA-seq revealed an obvious decrease in Vcam1 and Sox9 gene expression with Thy-1 knockdown. Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that the differentially expressed genes were enriched in the Wnt signalling pathway. We further demonstrated that Thy-1 knockdown promoted osteogenic differentiation of GMSCs by activating the Wnt/β-catenin signalling pathway. Therefore, Thy-1 has a key regulatory role in the differentiation of GMSCs and maybe a core molecule connecting transcription factors related to the differentiation of MSCs. Our study also highlighted the potential of Thy-1 to modify MSCs, which may help improve their use in tissue engineering.
Topics: beta Catenin; Cell Differentiation; Cells, Cultured; Mesenchymal Stem Cells; Osteogenesis; Wnt Signaling Pathway; Thy-1 Antigens
PubMed: 37786319
DOI: 10.1111/jcmm.17955 -
Transgenic murine models for the study of drug hypersensitivity reactions linked to HLA-I molecules.Current Opinion in Allergy and Clinical... Aug 2023Immune-mediated drug hypersensitivity reactions (DHRs) can be life-threatening and an impediment to drug development. Mechanism of disease studies are difficult to... (Review)
Review
PURPOSE OF REVIEW
Immune-mediated drug hypersensitivity reactions (DHRs) can be life-threatening and an impediment to drug development. Mechanism of disease studies are difficult to perform in humans. Here we review human leukocyte antigens class I (HLA-I) transgenic murine models and highlight how these systems have helped to elucidate drug-specific and host immune factors that initiate, propagate and control severe drug toxicities to skin and liver.
RECENT FINDINGS
HLA transgenic mice have been developed and used to study immune-mediated drug reactions in vitro and in vivo . CD8+ T cells from HLA-B∗57:01-expressing mice respond strongly to abacavir (ABC) in vitro but have self-limited responses to drug exposure in vivo . Immune tolerance can be overcome by depleting regulatory T cells (Treg) allowing antigen-presenting dendritic cells to express CD80/86 costimulatory molecules and signal through CD28 on the CD8+ T cell. Depletion of Treg also removes competition for interleukin 2 (IL-2) to allow T cell expansion and differentiation. Fine tuning of responses depends on inhibitory checkpoint molecules such as PD-1. Improved mouse models express only HLA in the absence of PD-1. These models show enhanced liver injury to flucloxacillin (FLX) which depends on drug priming, CD4+ T cell depletion, and lack of PD-1 expression. Drug-specific HLA-restricted cytotoxic CD8+ T cells can infiltrate the liver but are suppressed by Kupffer and liver sinusoidal endothelial cells.
SUMMARY
HLA-I transgenic mouse models are now available to study ABC, FLX and carbamazepine-induced adverse reactions. In vivo studies range from characterizing drug-antigen presentation, T cell activation, immune-regulatory molecules and cell-cell interaction pathways that are specifically involved in causing or controlling unwanted DHRs.
Topics: Mice; Humans; Animals; Disease Models, Animal; Programmed Cell Death 1 Receptor; Endothelial Cells; Drug Hypersensitivity; Mice, Transgenic; CD8-Positive T-Lymphocytes; Drug-Related Side Effects and Adverse Reactions
PubMed: 37284777
DOI: 10.1097/ACI.0000000000000913