RÉSUMÉ
Kidney failures in infants are mostly caused by congenital anomalies of the kidney and urinary tract (CAKUT), which are among the most common congenital birth disorders worldwide when paired with cardiac abnormalities. People with CAKUT often have severe kidney failure as a result of a wide range of abnormalities that can occur alone or in conjunction with other syndromic disorders. In this study, we aimed to investigate the expression pattern of CAKUT candidate genes alpha-8 integrin (ITGA8) and Van Gogh-like 2 (VANGL2) in fetal tissues of healthy and CAKUT-affected kidneys using immunohistochemistry and immunofluorescence. We found that under CAKUT circumstances, the expressions of ITGA8 and VANGL2 are changed. Additionally, we showed that VANGL2 expression is constant during fetal aging, but ITGA8 expression varies. Moreover, compared to normal healthy kidneys (CTRL), ITGA8 is poorly expressed in duplex kidneys (DKs) and dysplastic kidneys (DYS), whereas VANGL2 is substantially expressed in dysplastic kidneys (DYS) and poorly expressed in hypoplastic kidneys (HYP). These results point to VANGL2 and ITGA8 as potential prognostic indicators for CAKUT malformations. Further research is necessary to explore the molecular mechanisms underlying this differential expression of ITGA8 and VANGL2.
Sujet(s)
Intégrines alpha , Rein , Humains , Rein/métabolisme , Rein/malformations , Intégrines alpha/métabolisme , Intégrines alpha/génétique , Reflux vésico-urétéral/métabolisme , Reflux vésico-urétéral/génétique , Malformations urogénitales/métabolisme , Malformations urogénitales/génétique , Protéines membranaires/métabolisme , Protéines membranaires/génétique , Femelle , Voies urinaires/métabolisme , Voies urinaires/malformations , MâleRÉSUMÉ
Although oral tolerance is a critical system in regulating allergic disorders, the mechanisms by which dietary factors regulate the induction and maintenance of oral tolerance remain unclear. To address this, we explored the differentiation and function of various immune cells in the intestinal immune system under fasting and ad libitum-fed conditions before oral ovalbumin (OVA) administration. Fasting mitigated OVA-specific Treg expansion, which is essential for oral tolerance induction. This abnormality mainly resulted from functional defects in the CX3CR1+ cells responsible for the uptake of luminal OVA and reduction of tolerogenic CD103+ dendritic cells. Eventually, fasting impaired the preventive effect of oral OVA administration on asthma and allergic rhinitis development. Specific food ingredients, namely carbohydrates and arginine, were indispensable for oral tolerance induction by activating glycolysis and mTOR signaling. Overall, prior food intake and nutritional signals are critical for maintaining immune homeostasis by inducing tolerance to ingested food antigens.
Sujet(s)
Arginine , Cellules dendritiques , Tolérance immunitaire , Ovalbumine , Lymphocytes T régulateurs , Sérine-thréonine kinases TOR , Animaux , Arginine/métabolisme , Lymphocytes T régulateurs/immunologie , Ovalbumine/immunologie , Cellules dendritiques/immunologie , Cellules dendritiques/métabolisme , Souris , Sérine-thréonine kinases TOR/métabolisme , Souris de lignée C57BL , Administration par voie orale , Récepteur-1 de la chimiokine CX3C/métabolisme , Intestins/immunologie , Antigènes CD/métabolisme , Intégrines alpha/métabolisme , Sucres/métabolisme , Glycolyse , Jeûne , Transduction du signal , Muqueuse intestinale/immunologie , Muqueuse intestinale/métabolisme , FemelleRÉSUMÉ
BACKGROUND: Tissue-resident memory CD103+CD8+ T cells (CD103+CD8+ TRMs) are important components of anti-tumor immunity. However, the significance of CD103+CD8+ TRMs in colorectal cancer (CRC) and their advantages remain unclear. METHODS: Clinical data and specimens were used to evaluate the significance of CD103+CD8+ TRMs in CRC. A mouse subcutaneous tumorigenesis model and colony-formation assay were conducted to evaluate the anti-tumor effects of CD103+CD8+ TRMs. Finally, the infiltration density and function of CD103+CD8+ TRMs in the tumors were evaluated using flow cytometry. RESULTS: In this study, we showed that highly infiltrated CD103+CD8+ TRMs were associated with earlier clinical stage and negative VEGF expression in CRC patients and predicted a favorable prognosis for CRC/CRC liver metastases patients. Interestingly, we also found that CD103+CD8+ TRMs may have predictive potential for whether CRC develops liver metastasis in CRC. In addition, we found a positive correlation between the ratio of the number of α-SMA+ vessels to the sum of the number of α-SMA+ and CD31+ vessels in CRC, and the infiltration level of CD103+CD8+ TRMs. In addition, anti-angiogenic therapy promoted infiltration of CD103+CD8+ TRMs and enhanced their ability to secrete interferon (IFN)-γ, thus further improving the anti-tumor effect. Moreover, in vivo experiments showed that compared with peripheral blood CD8+ T cells, CD103+CD8+ TRMs infused back into the body could also further promote CD8+ T cells to infiltrate the tumor, and they had a stronger ability to secrete IFN-γ, which resulted in better anti-tumor effects. CONCLUSION: We demonstrated that CD103+CD8+ TRMs have the potential for clinical applications and provide new ideas for combined anti-tumor therapeutic strategies, such as anti-tumor angiogenesis therapy and CAR-T combined immunotherapy.
Sujet(s)
Antigènes CD , Lymphocytes T CD8+ , Tumeurs colorectales , Mémoire immunologique , Intégrines alpha , Tumeurs du foie , Tumeurs colorectales/immunologie , Tumeurs colorectales/anatomopathologie , Intégrines alpha/métabolisme , Intégrines alpha/immunologie , Animaux , Humains , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/métabolisme , Souris , Tumeurs du foie/immunologie , Tumeurs du foie/secondaire , Antigènes CD/métabolisme , Pronostic , Femelle , Mâle , Marqueurs biologiques tumoraux/métabolisme , Cellules T mémoire/immunologie , Cellules T mémoire/métabolisme , Lymphocytes TIL/immunologie , Lymphocytes TIL/métabolisme , Adulte d'âge moyenRÉSUMÉ
Leukemia stem cells (LSCs) are widely believed to reside in well-characterized bone marrow (BM) niches; however, the capacity of the BM niches to accommodate LSCs is insufficient, and a significant proportion of LSCs are instead maintained in regions outside the BM. The molecular basis for this niche-independent behavior of LSCs remains elusive. Here, we show that integrin-α9 overexpression (ITGA9 OE) plays a pivotal role in the extramedullary maintenance of LSCs by molecularly mimicking the niche-interacting status, through the binding with its soluble ligand, osteopontin (OPN). Retroviral insertional mutagenesis conducted on leukemia-prone Runx-deficient mice identified Itga9 OE as a novel leukemogenic event. Itga9 OE activates Akt and p38MAPK signaling pathways. The elevated Myc expression subsequently enhances ribosomal biogenesis to overcome the cell integrity defect caused by the preexisting Runx alteration. The Itga9-Myc axis, originally discovered in mice, was further confirmed in multiple human acute myeloid leukemia (AML) subtypes, other than RUNX leukemias. In addition, ITGA9 was shown to be a functional LSC marker of the best prognostic value among 14 known LSC markers tested. Notably, the binding of ITGA9 with soluble OPN, a known negative regulator against HSC activation, induced LSC dormancy, while the disruption of ITGA9-soluble OPN interaction caused rapid cell propagation. These findings suggest that the ITGA9 OE increases both actively proliferating leukemia cells and dormant LSCs in a well-balanced manner, thereby maintaining LSCs. The ITGA9 OE would serve as a novel therapeutic target in AML.
Sujet(s)
Leucémie aigüe myéloïde , Cellules souches tumorales , Animaux , Leucémie aigüe myéloïde/génétique , Leucémie aigüe myéloïde/métabolisme , Leucémie aigüe myéloïde/anatomopathologie , Humains , Souris , Cellules souches tumorales/métabolisme , Cellules souches tumorales/anatomopathologie , Ostéopontine/génétique , Ostéopontine/métabolisme , Niche de cellules souches , Intégrines alpha/métabolisme , Intégrines alpha/génétique , Protéines proto-oncogènes c-myc/métabolisme , Protéines proto-oncogènes c-myc/génétique , Régulation de l'expression des gènes dans la leucémie , Sous-unité alpha 2 du facteur CBF/génétique , Sous-unité alpha 2 du facteur CBF/métabolisme , Souris de lignée C57BL , Transduction du signalRÉSUMÉ
Lung-tissue-resident memory (TRM) CD8+ T cells are critical for heterosubtypic immunity against influenza virus (IAV) reinfection. How TRM cells surveil the lung, respond to infection, and interact with other cells remains unresolved. Here, we used IAV infection of mice in combination with intravital and static imaging to define the spatiotemporal dynamics of lung TRM cells before and after recall infection. CD69+CD103+ TRM cells preferentially localized to lung sites of prior IAV infection, where they exhibited patrolling behavior. After rechallenge, lung TRM cells formed tight clusters in an antigen-dependent manner. Transcriptomic analysis of IAV-specific TRM cells revealed the expression of several factors that regulate myeloid cell biology. In vivo rechallenge experiments demonstrated that protection elicited by TRM cells is orchestrated in part by interferon (IFN)-γ-mediated recruitment of inflammatory monocytes into the lungs. Overall, these data illustrate the dynamic landscapes of CD103+ lung TRM cells that mediate early protective immunity against IAV infection.
Sujet(s)
Antigènes CD , Lymphocytes T CD8+ , Mémoire immunologique , Virus de la grippe A , Intégrines alpha , Poumon , Cellules T mémoire , Infections à Orthomyxoviridae , Animaux , Poumon/immunologie , Poumon/virologie , Infections à Orthomyxoviridae/immunologie , Lymphocytes T CD8+/immunologie , Souris , Mémoire immunologique/immunologie , Intégrines alpha/métabolisme , Virus de la grippe A/immunologie , Antigènes CD/métabolisme , Cellules T mémoire/immunologie , Souris de lignée C57BL , Interféron gamma/métabolisme , Interféron gamma/immunologie , Microscopie intravitale , Monocytes/immunologieRÉSUMÉ
Chronic rhinosinusitis with nasal polyps (CRSwNPs) is a heterogeneous disease characterized by local inflammation of the upper airway and sinus mucosa. T cell-mediated immune responses play irreplaceable roles in the pathogenesis of nasal polyps. CD161+ T cells have been implicated in the pathology of several diseases through cytokine production and cytotoxic activity. However, the immunological characteristics of CD161+ T cells in nasal mucosa are still not well understood, particularly in CRSwNPs. Our research revealed a notable enrichment of CD161+ T cells in nasal tissues compared to peripheral blood, with a significantly more infiltration of CD161+ T cells in CRSwNPs compared to control nasal samples. Phenotypical analysis found that CD161+ T cells predominantly co-expressed tissue-resident memory surface markers CD103, CD69, and CD45RO. CD161+CD103+ T cells demonstrated complicated effector functions, marked by elevated levels of PD-1, CTLA-4, IL-17, and IFN-γ and diminished expression of FoxP3 and CD25. Interestingly, despite CD161+ T cells was more abundant in polyp tissues compared to normal control tissues, and then further categorizing polyp samples into distinct groups based on clinical characteristics, only the recurrent CRSwNP group showed a significant reduction in CD161+CD8+ T cells compared to the primary CRSwNP group. This finding suggested the necessity for further research to comprehensively understand the underlying mechanisms and the broader significance of CD161+ T cells in the advancement and relapse of CRSwNPs.
Sujet(s)
Antigènes CD , Intégrines alpha , Sous-famille B des récepteurs de cellules NK de type lectine , Polypes du nez , , Adulte , Femelle , Humains , Mâle , Adulte d'âge moyen , Antigènes CD/métabolisme , Antigènes CD/immunologie , Antigènes de différenciation des lymphocytes T/métabolisme , Antigènes de différenciation des lymphocytes T/immunologie , Maladie chronique , Antigène CTLA-4/métabolisme , Antigène CTLA-4/immunologie , Intégrines alpha/métabolisme , Intégrines alpha/immunologie , Interféron gamma/métabolisme , Interféron gamma/immunologie , Interleukine-17/métabolisme , Interleukine-17/immunologie , Lectines de type C , Muqueuse nasale/immunologie , Polypes du nez/immunologie , Sous-famille B des récepteurs de cellules NK de type lectine/métabolisme , Sous-famille B des récepteurs de cellules NK de type lectine/immunologie , /immunologie , Lymphocytes T/immunologie , Lymphocytes T/métabolismeRÉSUMÉ
Men who have sex with men (MSM) with HIV are at high risk for squamous intraepithelial lesion (SIL) and anal cancer. Identifying local immunological mechanisms involved in the development of anal dysplasia could aid treatment and diagnostics. Here, we studied 111 anal biopsies obtained from 101 MSM with HIV, who participated in an anal screening program. We first assessed multiple immune subsets by flow cytometry, in addition to histological examination, in a discovery cohort. Selected molecules were further evaluated by immunohistochemistry in a validation cohort. Pathological samples were characterized by the presence of resident memory T cells with low expression of CD103 and by changes in natural killer cell subsets, affecting residency and activation. Furthermore, potentially immunosuppressive subsets, including CD15+CD16+ mature neutrophils, gradually increased as the anal lesion progressed. Immunohistochemistry verified the association between the presence of CD15 in the epithelium and SIL diagnosis for the correlation with high-grade SIL. A complex immunological environment with imbalanced proportions of resident effectors and immune-suppressive subsets characterized pathological samples. Neutrophil infiltration, determined by CD15 staining, may represent a valuable pathological marker associated with the grade of dysplasia.
Sujet(s)
Tumeurs de l'anus , Infections à VIH , Antigènes CD15 , Humains , Mâle , Infections à VIH/immunologie , Infections à VIH/complications , Infections à VIH/anatomopathologie , Tumeurs de l'anus/anatomopathologie , Tumeurs de l'anus/immunologie , Adulte , Adulte d'âge moyen , Antigènes CD15/métabolisme , Homosexualité masculine , Lésions malpighiennes intra-épithéliales/anatomopathologie , Canal anal/anatomopathologie , Cellules tueuses naturelles/immunologie , Cellules tueuses naturelles/métabolisme , Antigènes CD/métabolisme , Granulocytes neutrophiles/immunologie , Granulocytes neutrophiles/anatomopathologie , Granulocytes neutrophiles/métabolisme , Biopsie , Immunohistochimie , Intégrines alpha/métabolismeRÉSUMÉ
Unlike T cells in other tissues, uterine T cells must balance strong immune defense against pathogens with tolerance to semiallogeneic fetus. Our previous study fully elucidated the characteristics of γδT cells in nonpregnant uterus and the mechanism modulated by estrogen. However, comprehensive knowledge of the immunological properties of αßT (including CD4+T cells and CD8+T) cells in nonpregnancy uterus has not been acquired. In this study, we fully compared the immunological properties of αßT cells between uterus and blood using mouse and human sample. It showed that most of CD4+T cells and CD8+T cells in murine uterus and human endometrium were tissue resident memory T cells which highly expressed tissue residence markers CD69 and/or CD103. In addition, both CD4+T cells and CD8+T cells in uterus highly expressed inhibitory molecular PD-1 and cytokine IFN-γ. Uterine CD4+T cells highly expressed IL-17 and modulated by transcription factor pSTAT3. Moreover, we compared the similarities and differences between human and murine uterine T cell phenotype. Together, uterine CD4+T cells and CD8+ cells exhibited a unique mixed signature of T cell dysfunction, activation, and effector function which enabled them to balance strong immune defense against pathogens with tolerance to fetus. Our study fully elucidated the unique immunologic properties of uterine CD4+T and CD8+T cells and provided a base for further investigation of functions.
Sujet(s)
Antigènes CD , Lymphocytes T CD4+ , Lymphocytes T CD8+ , Utérus , Femelle , Lymphocytes T CD8+/immunologie , Animaux , Humains , Souris , Lymphocytes T CD4+/immunologie , Utérus/immunologie , Antigènes CD/métabolisme , Récepteur-1 de mort cellulaire programmée/métabolisme , Récepteur-1 de mort cellulaire programmée/génétique , Intégrines alpha/métabolisme , Cellules T mémoire/immunologie , Facteur de transcription STAT-3/métabolisme , Interféron gamma/métabolisme , Lectines de type C/métabolisme , Antigènes de différenciation des lymphocytes T/métabolisme , Interleukine-17/métabolisme , Activation des lymphocytes/immunologie , Mémoire immunologiqueRÉSUMÉ
Transforming growth factor ß (TGF-ß) represents a well-established signal required for tissue-resident memory T cell (TRM) formation at intestinal surfaces, regulating the expression of a large collection of genes coordinately promoting intestinal TRM differentiation. The functional contribution from each TGF-ß-controlled transcription factor is not entirely known. Here, we find that TGF-ß-induced T-bet downregulation and Hic1 induction represent two critical events during intestinal TRM differentiation. Importantly, T-bet deficiency significantly rescues intestinal TRM formation in the absence of the TGF-ß receptor. Hic1 induction further strengthens TRM maturation in the absence of TGF-ß and T-bet. Our results reveal that provision of certain TGF-ß-induced molecular events can partially replace TGF-ß signaling to promote the establishment of intestinal TRMs, which allows the functional dissection of TGF-ß-induced transcriptional targets and molecular mechanisms for TRM differentiation.
Sujet(s)
Lymphocytes T CD8+ , Muqueuse intestinale , Facteurs de transcription Krüppel-like , Transduction du signal , Protéines à domaine boîte-T , Animaux , Souris , Antigènes CD/métabolisme , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/métabolisme , Différenciation cellulaire , Mémoire immunologique , Intégrines alpha/métabolisme , Muqueuse intestinale/cytologie , Muqueuse intestinale/immunologie , Muqueuse intestinale/métabolisme , Intestins/immunologie , Facteurs de transcription Krüppel-like/métabolisme , Cellules T mémoire/métabolisme , Cellules T mémoire/immunologie , Souris de lignée C57BL , Protéines à domaine boîte-T/métabolisme , Protéines à domaine boîte-T/génétique , Facteur de croissance transformant bêta/métabolismeRÉSUMÉ
Resident memory T cells (TRMs) help control local immune homeostasis and contribute to tissue-protective immune responses. The local cues that guide their differentiation and localization are poorly defined. We demonstrate that mucosal vascular addressin cell adhesion molecule 1, a ligand for the gut-homing receptor α4ß7 integrin, in the presence of retinoic acid and transforming growth factor-ß (TGF-ß) provides a co-stimulatory signal that induces blood cluster of differentiation (CD8+ T cells to adopt a TRM-like phenotype. These cells express CD103 (integrin αE) and CD69, the two major TRM cell-surface markers, along with CD101. They also express C-C motif chemokine receptors 5 (CCR5) , C-C motif chemokine receptors 9 (CCR9), and α4ß7, three receptors associated with gut homing. A subset also expresses E-cadherin, a ligand for αEß7. Fluorescent lifetime imaging indicated an αEß7 and E-cadherin cis interaction on the plasma membrane. This report advances our understanding of the signals that drive the differentiation of CD8+ T cells into resident memory T cells and provides a means to expand these cells in vitro, thereby affording an avenue to generate more effective tissue-specific immunotherapies.
Sujet(s)
Antigènes CD , Antigènes de différenciation des lymphocytes T , Lymphocytes T CD8+ , Intégrines alpha , Facteur de croissance transformant bêta , Trétinoïne , Trétinoïne/pharmacologie , Animaux , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/métabolisme , Souris , Intégrines alpha/métabolisme , Facteur de croissance transformant bêta/métabolisme , Antigènes CD/métabolisme , Antigènes de différenciation des lymphocytes T/métabolisme , Mémoire immunologique , Molécules d'adhérence cellulaire/métabolisme , Cadhérines/métabolisme , Lectines de type C/métabolisme , Différenciation cellulaire , Mucoprotéines/métabolisme , Récepteurs CCR/métabolisme , Cellules T mémoire/immunologie , Cellules T mémoire/métabolisme , Immunoglobulines/métabolisme , Souris de lignée C57BL , Muqueuse intestinale/immunologie , Muqueuse intestinale/métabolisme , Intégrines/métabolisme , PhénotypeRÉSUMÉ
Tumor-associated macrophages of the M2 phenotype promote cancer initiation and progression. Importantly, M2 macrophage-derived exosomes play key roles in the malignancy of cancer cells. Here, we report that circTMCO3 is upregulated in ovarian cancer patients, and its high expression indicates poor survival. M2-derived exosomes promote proliferation, migration, and invasion in ovarian cancer, but these effects are abolished by knockdown of circTMCO3. Furthermore, circTMCO3 functions as a competing endogenous RNA for miR-515-5p to reduce its abundance, thus upregulating ITGA8 in ovarian cancer. miR-515-5p inhibits ovarian cancer malignancy via directly downregulating ITGA8. The decreased oncogenic activity of circTMCO3-silencing exosomes is reversed by miR-515-5p knockdown or ITGA8 overexpression. Exosomal circTMCO3 promotes ovarian cancer progression in nude mice. Thus, M2 macrophage-derived exosomes promote malignancy by delivering circTMCO3 and targeting the miR-515-5p/ITGA8 axis in ovarian cancer. Our findings not only provide mechanistic insights into ovarian cancer progression, but also suggest potential therapeutic targets.
Sujet(s)
Exosomes , Intégrines alpha , Macrophages , microARN , Tumeurs de l'ovaire , ARN circulaire , Animaux , Femelle , Humains , Souris , Lignée cellulaire tumorale , Mouvement cellulaire , Prolifération cellulaire , Exosomes/métabolisme , Exosomes/génétique , Régulation de l'expression des gènes tumoraux , Intégrines alpha/génétique , Intégrines alpha/métabolisme , Macrophages/métabolisme , Souris nude , microARN/génétique , microARN/métabolisme , Tumeurs de l'ovaire/génétique , Tumeurs de l'ovaire/anatomopathologie , Tumeurs de l'ovaire/métabolisme , ARN circulaire/génétique , ARN circulaire/métabolismeRÉSUMÉ
BACKGROUND: Psoriasis is a T cell-mediated chronic inflammatory skin condition characterized by the interaction of T cells with various cell types, forming an inflammatory microenvironment that sustains psoriatic inflammation. Homeostasis of these tissue-resident T cells is supported by fibroblasts, the primary structural cells in the dermis. In psoriasis, there is increased expression of matrix metalloproteinase 2 (MMP2), mediating structural alterations in skin tissues and modulating inflammation. Additionally, the CD100-plexin-B2 (PLXNB2) axis is known to enhance psoriasis inflammation via keratinocytes, and CD103 levels are associated with the severity of psoriasis upon relapse. OBJECTIVES: To elucidate the role of fibroblasts and the MMP2-CD100 axis in modulating psoriasis inflammation. METHODS: CD100 expression and function in psoriasis were assessed using immunofluorescence, enzyme-linked immunosorbent assay, single-cell transcriptome sequencing, cellular interaction analyses and quantitative reverse transcriptase polymerase chain reaction. CD8+ T cells from people with psoriasis were isolated using magnetic beads, to investigate the regulatory effect of MMP2 on CD100 expression on their membranes. Single-cell transcriptome sequencing, spatial transcriptome sequencing, mimetic timing analysis, immunofluorescence and flow cytometry were used to determine the origin of MMP2 and its impact on CD103+ CD8+ T cells. The hypotheses were further validated in vivo using MMP2 and CD100 inhibitors. RESULTS: Soluble CD100 (sCD100) was significantly upregulated in both psoriatic lesions and peripheral blood, amplifying psoriasis inflammation by promoting the production of inflammatory cytokines by keratinocytes, fibroblasts and endothelial cells via the sCD100-PLXNB2 axis. Fibroblasts that highly expressed MMP2 (MMP2hi) exacerbated psoriasis symptoms by facilitating CD100 shedding from CD8+ T-cell membranes. Additionally, it was shown that fibroblasts enhance the upregulation of the CD8+ T-cell residency factor CD103 in co-cultures with CD8+ T cells. Inhibitors targeting MMP2 and CD100 were effective in reducing inflammation in an imiquimod-induced psoriasis model. CONCLUSIONS: Our findings underscore the pivotal role of MMP2hi fibroblasts in the amplification and recurrence of inflammatory responses in psoriasis. These fibroblasts augment psoriasis inflammation through the CD100-PLXNB2 axis by facilitating CD100 shedding on CD8+ T-cell membranes and by upregulating CD103, thereby enhancing CD8+ T-cell residency.
Psoriasis is a chronic skin condition. It involves the interaction of cells of the immune system (called T cells) with other cells in the body, causing inflammation. The main structural cells in the skin are called fibroblasts. Fibroblasts are important in skin healing and disease. In psoriasis, the body produces more of an enzyme called MMP2. MMP2 brings about structural alterations in skin tissues and controls inflammation. Proteins called CD100 and PLXNB2 increase the inflammation in psoriasis through another type of skin cell called keratinocytes. We investigated the role of fibroblasts and MMP2 and CD100 in psoriasis. To do this, the production and function of CD100 were assessed using a variety of laboratory techniques. We found that by controlling the enzymes MMP2 and MMP9, fibroblasts cause the release of CD100 from some T cells, encouraging the production of substances that promote inflammation, worsening psoriasis. This also caused fibroblasts to produce more MMP2, forming a cycle that increases the inflammation seen in psoriasis. Fibroblasts were found to increase the level of another protein called CD103 on some T cells, affecting how often psoriasis flares up. Our study highlights the important role of fibroblasts that express a lot of MMP2 in the inflammation found in people with psoriasis.
Sujet(s)
Antigènes CD , Lymphocytes T CD8+ , Fibroblastes , Matrix metalloproteinase 2 , Psoriasis , Psoriasis/immunologie , Humains , Lymphocytes T CD8+/immunologie , Lymphocytes T CD8+/métabolisme , Fibroblastes/métabolisme , Matrix metalloproteinase 2/métabolisme , Antigènes CD/métabolisme , Souris , Animaux , Kératinocytes/métabolisme , Mâle , Femelle , Peau/immunologie , Peau/anatomopathologie , Intégrines alpha/métabolisme , Cellules cultivées , SémaphorinesRÉSUMÉ
The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens1,2. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (Treg) cell development and function have been identified3,4, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive Treg cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing5-7 and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector Treg (eTreg) cell function. eTreg cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103+SIRPα+ dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206+ macrophages and eTreg cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.
Sujet(s)
Muqueuse intestinale , Muqueuse , Lymphocytes T régulateurs , Animaux , Femelle , Mâle , Souris , Antigènes CD/métabolisme , Cellules dendritiques/immunologie , Cellules dendritiques/métabolisme , Analyse de profil d'expression de gènes , Helicobacter hepaticus/immunologie , Infections à Helicobacter/immunologie , Infections à Helicobacter/microbiologie , Tolérance immunitaire/immunologie , Inflammation/immunologie , Inflammation/microbiologie , Inflammation/anatomopathologie , Intégrines alpha/métabolisme , Muqueuse intestinale/cytologie , Muqueuse intestinale/immunologie , Macrophages/immunologie , Macrophages/métabolisme , Souris de lignée C57BL , Muqueuse/cytologie , Muqueuse/immunologie , Récepteurs immunologiques/métabolisme , Récepteurs immunologiques/immunologie , Analyse de l'expression du gène de la cellule unique , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/cytologie , TranscriptomeRÉSUMÉ
Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.
Sujet(s)
Antigènes CD , Apyrase , Intégrines alpha , Récepteurs aux antigènes des cellules T , Transduction du signal , Animaux , Humains , Souris , Antigènes CD/métabolisme , Antigènes CD/immunologie , Lignée cellulaire tumorale , Cytotoxicité immunologique , Intégrines alpha/métabolisme , Lymphocytes TIL/immunologie , Lymphocytes TIL/métabolisme , Tumeurs/immunologie , Tumeurs/thérapie , Récepteurs aux antigènes des cellules T/métabolisme , Récepteurs aux antigènes des cellules T/immunologie , Transduction du signal/immunologie , Lymphocytes T cytotoxiques/immunologieRÉSUMÉ
Chitin and its derivative chitosan (Q) are abundant structural elements in nature. Q has modulatory and anti-inflammatory effects and also regulates the expression of adhesion molecules. The interaction between cells expressing the αEß7 integrin and E-cadherin facilitates tolerogenic signal transmission and localization of lymphocytes at the frontline for interaction with luminal antigens. In this study we evaluated the ability of orally administered Q to stimulate E-cadherin and CD103 expression in vitro and in vivo. Our findings show that Q promoted epithelial cell migration, accelerated wound healing and increased E-cadherin expression in IEC-18 cells and isolated intestinal epithelial cells (IECs) after Q feeding. The upregulation of E-cadherin was dependent on TLR4 and IFNAR signaling, triggering CD103 expression in lymphocytes. Q reinforced the E-cadherin-αEß7 axis, crucial for intestinal barrier integrity and contributed to the localization of lymphocytes on the epithelium.
Sujet(s)
Antigènes CD , Cadhérines , Chitosane , Intégrines alpha , Muqueuse intestinale , Transduction du signal , Récepteur de type Toll-4 , Animaux , Récepteur de type Toll-4/métabolisme , Chitosane/pharmacologie , Chitosane/composition chimique , Cadhérines/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Intégrines alpha/métabolisme , Souris , Antigènes CD/métabolisme , Muqueuse intestinale/métabolisme , Muqueuse intestinale/effets des médicaments et des substances chimiques , Mouvement cellulaire/effets des médicaments et des substances chimiques , Lignée cellulaire , Intestins/effets des médicaments et des substances chimiques , Rats , MâleRÉSUMÉ
BACKGROUND: Machine perfusion is the preferred preservation method for deceased donor kidneys. Perfusate fluid, which contains a complex mixture of components, offers potential insight into the organ's viability and function. This study explored immune cell release, particularly tissue-resident lymphocytes (TRLs), during donor kidney machine perfusion and its correlation with injury markers. METHODS: Perfusate samples from hypothermic machine perfusion (HMP; nâ =â 26) and normothermic machine perfusion (NMP; nâ =â 16) of human donor kidneys were analyzed for TRLs using flow cytometry. Residency was defined by expressions of CD69, CD103, and CD49as. TRL release was quantified exclusively in NMP. Additionally, levels of cell-free DNA, neutrophil gelatinase-associated lipocalin, and soluble E-cadherin (sE-cadherin) were measured in NMP supernatants with quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Both HMP and NMP samples contained a heterogeneous population of TRLs, including CD4 + tissue-resident memory T cells, CD8 + tissue-resident memory T cells, tissue-resident natural killer cells, tissue-resident natural killer T cells, and helper-like innate lymphoid cells. Median TRL proportions among total CD45 + lymphocytes were 0.89% (NMP) and 0.84% (HMP). TRL quantities in NMP did not correlate with donor characteristics, perfusion parameters, posttransplant outcomes, or cell-free DNA and neutrophil gelatinase-associated lipocalin concentrations. However, CD103 + TRL release positively correlated with the release of sE-cadherin, the ligand for the CD103 integrin. CONCLUSIONS: Human donor kidneys release TRLs during both HMP and NMP. The release of CD103 + TRLs was associated with the loss of their ligand sE-cadherin but not with general transplant injury biomarkers.
Sujet(s)
Antigènes CD , Transplantation rénale , Rein , Lipocaline-2 , Conservation d'organe , Perfusion , Humains , Transplantation rénale/méthodes , Perfusion/méthodes , Mâle , Adulte d'âge moyen , Femelle , Lipocaline-2/métabolisme , Lipocaline-2/analyse , Adulte , Conservation d'organe/méthodes , Antigènes CD/métabolisme , Rein/immunologie , Rein/vascularisation , Donneurs de tissus , Lymphocytes/immunologie , Lymphocytes/métabolisme , Marqueurs biologiques/métabolisme , Cadhérines/métabolisme , Sujet âgé , Intégrines alpha/métabolisme , Cytométrie en flux , Lipocalines/métabolisme , Hypothermie provoquéeSujet(s)
Antigènes CD , Intégrines alpha , Animaux , Antigènes CD/immunologie , Antigènes CD/métabolisme , Intégrines alpha/métabolisme , Intégrines alpha/immunologie , Souris , Cytotoxicité immunologique , Humains , Lymphocytes T CD8+/immunologie , Synapses immunologiques/immunologie , Synapses immunologiques/métabolismeRÉSUMÉ
NK cells have been shown to exhibit inflammatory and immunoregulatory functions in a variety of healthy and diseased settings. In the context of chronic viral infection and cancer, distinct NK cell populations that inhibit adaptive immune responses have been observed. To understand how these cells arise and further characterize their immunosuppressive role, we examined in vitro conditions that could polarize human NK cells into an inhibitory subset. TGF-ß1 has been shown to induce regulatory T cells in vitro and in vivo; we therefore investigated if TGF-ß1 could also induce immunosuppressive NK-like cells. First, we found that TGF-ß1/IL-15, but not IL-15 alone, induced CD103+CD49a+ NK-like cells from peripheral blood NK cells, which expressed markers previously associated with inhibitory CD56+ innate lymphoid cells, including high expression of GITR and CD101. Moreover, supernatant from ascites collected from patients with ovarian carcinoma also induced CD103+CD49a+ NK-like cells in vitro in a TGF-ß-dependent manner. Interestingly, TGF-ß1/IL-15-induced CD103+CD56+ NK-like cells suppressed autologous CD4+ T cells in vitro by reducing absolute number, proliferation, and expression of activation marker CD25. Collectively, these findings provide new insight into how NK cells may acquire an inhibitory phenotype in TGF-ß1-rich environments.
Sujet(s)
Interleukine-15 , Cellules tueuses naturelles , Facteur de croissance transformant bêta-1 , Humains , Cellules tueuses naturelles/immunologie , Interleukine-15/immunologie , Interleukine-15/métabolisme , Facteur de croissance transformant bêta-1/métabolisme , Femelle , Antigènes CD/métabolisme , Antigènes CD/immunologie , Tumeurs de l'ovaire/immunologie , Tumeurs de l'ovaire/anatomopathologie , Intégrines alpha/métabolisme , Intégrines alpha/immunologie , Antigènes CD56/métabolisme , Cellules cultivées , Sous-populations de lymphocytes/immunologie , Sous-populations de lymphocytes/métabolisme , Activation des lymphocytes/immunologieRÉSUMÉ
The active vitamin A metabolite, all-trans-retinoic acid (RA), primes precursor dendritic cells (DCs) into a mucosal phenotype with tolerogenic properties characterized by the expression of integrin CD103. CD103+ DCs can counteract pathogenic Th1 and Th17 in inflammatory bowel disease (IBD) or celiac disease (CD). Tolerogenic manipulation of DCs using nanoparticles carrying tolerogenic adjuvants and disease-specific antigens is a valuable treatment strategy to induce antigen-specific mucosal tolerance in vivo. Here, we investigated the effects of RA-loaded liposomes on human DC phenotype and function, including DC-driven T-cell development, both during the generation of monocyte-derived DCs (moDCs) as well as by priming immature moDCs. RA liposomes drove CD103+ DC differentiation as well as ALDH1A2 expression in DCs. Neutrophil-dependent Th17 cell development was reduced by RA-liposome-differentiated and RA-liposome-primed DCs. Moreover, RA liposome treatment shifted T-cell development toward a Th2 cell profile. Importantly, RA liposomes induced the development of IL-10-producing and FoxP3+ regulatory T cells (Tregs) of various Treg subsets, including ICOS+ Tregs, that were potent inhibitors of bystander memory T-cell proliferation. Taken together, RA-loaded liposomes could be a novel treatment avenue for IBD or CD patients.
Sujet(s)
Aldéhyde déshydrogénase-1 , Antigènes CD , Différenciation cellulaire , Cellules dendritiques , Intégrines alpha , Liposomes , Retinal dehydrogenase , Lymphocytes T régulateurs , Cellules Th17 , Trétinoïne , Humains , Trétinoïne/pharmacologie , Intégrines alpha/métabolisme , Cellules Th17/immunologie , Cellules dendritiques/immunologie , Cellules dendritiques/effets des médicaments et des substances chimiques , Antigènes CD/immunologie , Antigènes CD/métabolisme , Lymphocytes T régulateurs/immunologie , Lymphocytes T régulateurs/effets des médicaments et des substances chimiques , Différenciation cellulaire/effets des médicaments et des substances chimiques , Différenciation cellulaire/immunologie , Retinal dehydrogenase/métabolisme , Tolérance immunitaire/effets des médicaments et des substances chimiques , Cellules cultivées , Interleukine-10/métabolisme , Interleukine-10/immunologie , Facteurs de transcription Forkhead/métabolisme , Maladies inflammatoires intestinales/immunologie , Activation des lymphocytes/effets des médicaments et des substances chimiques , Activation des lymphocytes/immunologie , Maladie coeliaque/immunologieRÉSUMÉ
Resident memory T (TRM) cells have been recently established as an important subset of memory T cells that provide early and essential protection against reinfection in the absence of circulating memory T cells. Recent findings showing that TRM expand in vivo after repeated antigenic stimulation indicate that these memory T cells are not terminally differentiated. This suggests an opportunity for in vitro TRM expansion to apply in an immunotherapy setting. However, it has also been shown that TRM may not maintain their identity and form circulating memory T cells after in vivo restimulation. Therefore, we set out to determine how TRM respond to antigenic activation in culture. Using Listeria monocytogenes and LCMV infection models, we found that TRM from the intraepithelial compartment of the small intestine expand in vitro after antigenic stimulation and subsequent resting in homeostatic cytokines. A large fraction of the expanded TRM retained their phenotype, including the expression of key TRM markers CD69 and CD103 (ITGAE). The optimal culture of TRM required low O2 pressure to maintain the expression of these and other TRM-associated molecules. Expanded TRM retained their effector capacity to produce cytokines after restimulation, but did not acquire a highly glycolytic profile indicative of effector T cells. The proteomic analysis confirmed TRM profile retention, including expression of TRM-related transcription factors, tissue retention factors, adhesion molecules, and enzymes involved in fatty acid metabolism. Collectively, our data indicate that limiting oxygen conditions supports in vitro expansion of TRM cells that maintain their TRM phenotype, at least in part, suggesting an opportunity for therapeutic strategies that require in vitro expansion of TRM.