scholarly journals Progranulin promotes immune evasion of pancreatic adenocarcinoma through regulation of MHCI expression

2021 ◽  
Author(s):  
Phyllis F Cheung ◽  
JiaJin Yang ◽  
Kirsten Krengel ◽  
Kristina Althoff ◽  
Chi Wai Yip ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Evasion ◽  
Ductal Adenocarcinoma ◽  
Antibody Treatment ◽  
Poor Overall Survival ◽  
Autonomous Function ◽  
Cancer Initiation ◽  
Specific Cytotoxicity ◽  
Underlying Mechanisms

ABSTRACTImmune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain elusive. Here, we unveiled a cancer cell-autonomous function of PGRN in driving immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN was associated with poor overall survival in PDAC. Multiplex immunohistochemistry revealed low MHC class I (MHCI) expression and lack of CD8+ T cells infiltration in PGRN-high tumors. Inhibition of PGRN abrogated autophagy-dependent MHCI degradation and restored MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a genetic PDAC mouse model remarkably decelerated tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as model antigen were sensitized towards cytotoxic gp33-TCR transgenic T cells upon anti-PGRN antibody treatment. Overall, our study uncovered an unprecedented role of tumor-derived PGRN in regulating immunogenicity of primary PDAC.STATEMENT OF SIGNIFICANCEImmune evasion is a key property of PDAC, rendering it refractory to immunotherapy. Here we demonstrate that tumor-derived PGRN promotes autophagy-dependent MHCI degradation, while anti-PGRN increases intratumoral CD8 infiltration and blocks tumor progression. With recent advances in T cell-mediated approaches, PGRN represents a pivotal target to enhance tumor antigen-specific cytotoxicity.

scholarly journals Progranulin mediates immune evasion of pancreatic ductal adenocarcinoma through regulation of MHCI expression

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Phyllis F. Cheung ◽  
JiaJin Yang ◽  
Rui Fang ◽  
Arianna Borgers ◽  
Kirsten Krengel ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Mhc Class I ◽  
Immune Evasion ◽  
Ductal Adenocarcinoma ◽  
Poor Overall Survival ◽  
T Cell Infiltration ◽  
Cancer Initiation ◽  
Underlying Mechanisms

AbstractImmune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) are not fully known. Here, we characterize the function of tumor-derived PGRN in promoting immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN is associated with poor overall survival in PDAC. Multiplex immunohistochemistry shows low MHC class I (MHCI) expression and lack of CD8+ T cell infiltration in PGRN-high tumors. Inhibition of PGRN abrogates autophagy-dependent MHCI degradation and restores MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a PDAC mouse model remarkably decelerates tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as a model antigen are sensitized to gp33-TCR transgenic T cell-mediated cytotoxicity upon PGRN blockade. Overall, our study shows a crucial function of tumor-derived PGRN in regulating immunogenicity of primary PDAC.

scholarly journals Role of T-cell activation in salt-sensitive hypertension

2019 ◽  
Vol 316 (6) ◽  
pp. H1345-H1353 ◽  
Author(s):  
Jiafa Ren ◽  
Steven D. Crowley
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
T Subsets ◽  
Underlying Mechanisms ◽  
Salt Sensitive Hypertension

The contributions of T lymphocytes to the pathogenesis of salt-sensitive hypertension has been well established. Under hypertensive stimuli, naive T cells develop into different subsets, including Th1, Th2, Th17, Treg, and cytotoxic CD8+ T cells, depending on the surrounding microenviroment in organs. Distinct subsets of T cells may play totally different roles in tissue damage and hypertension. The underlying mechanisms by which hypertensive stimuli activate naive T cells involve many events and different organs, such as neoantigen presentation by dendritic cells, high salt concentration, and the milieu of oxidative stress in the kidney and vasculature. Infiltrating and activated T subsets in injured organs, in turn, exert considerable impacts on tissue dysfunction, including sodium retention in the kidney, vascular stiffness, and remodeling in the vasculature. Therefore, a thorough knowledge of T-cell actions in hypertension may provide novel insights into the development of new therapeutic strategies for patients with hypertension.

scholarly journals T cell-intrinsic role of IL-6 signaling in primary and memory responses

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Simone A Nish ◽  
Dominik Schenten ◽  
F Thomas Wunderlich ◽  
Scott D Pope ◽  
Yan Gao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Suppressive Effect ◽  
Immune Recognition ◽  
Th17 Response ◽  
Cell Responses ◽  
Underlying Mechanisms ◽  
Specific Deletion

Innate immune recognition is critical for the induction of adaptive immune responses; however the underlying mechanisms remain incompletely understood. In this study, we demonstrate that T cell-specific deletion of the IL-6 receptor α chain (IL-6Rα) results in impaired Th1 and Th17 T cell responses in vivo, and a defect in Tfh function. Depletion of Tregs in these mice rescued the Th1 but not the Th17 response. Our data suggest that IL-6 signaling in effector T cells is required to overcome Treg-mediated suppression in vivo. We show that IL-6 cooperates with IL-1β to block the suppressive effect of Tregs on CD4+ T cells, at least in part by controlling their responsiveness to IL-2. In addition, although IL-6Rα-deficient T cells mount normal primary Th1 responses in the absence of Tregs, they fail to mature into functional memory cells, demonstrating a key role for IL-6 in CD4+ T cell memory formation.

scholarly journals Mycobacterium abscessuscording prevents phagocytosis and promotes abscess formation

2014 ◽  
Vol 111 (10) ◽  
pp. E943-E952 ◽  
Author(s):  
Audrey Bernut ◽  
Jean-Louis Herrmann ◽  
Karima Kissa ◽  
Jean-François Dubremetz ◽  
Jean-Louis Gaillard ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Wide Spectrum ◽  
Mycobacterium Abscessus ◽  
Abscess Formation ◽  
Zebrafish Embryos ◽  
Clinical Syndromes ◽  
The Central Nervous System ◽  
Underlying Mechanisms

Mycobacterium abscessusis a rapidly growingMycobacteriumcausing a wide spectrum of clinical syndromes. It now is recognized as a pulmonary pathogen to which cystic fibrosis patients have a particular susceptibility. TheM. abscessusrough (R) variant, devoid of cell-surface glycopeptidolipids (GPLs), causes more severe clinical disease than the smooth (S) variant, but the underlying mechanisms of R-variant virulence remain obscure. Exploiting the optical transparency of zebrafish embryos, we observed that the increased virulence of theM. abscessusR variant compared with the S variant correlated with the loss of GPL production. The virulence of the R variant involved the massive production of serpentine cords, absent during S-variant infection, and the cords initiated abscess formation leading to rapid larval death. Cording occurred within the vasculature and was highly pronounced in the central nervous system (CNS). It appears thatM. abscessusis transported to the CNS within macrophages. The release ofM. abscessusfrom apoptotic macrophages initiated the formation of cords that grew too large to be phagocytized by macrophages or neutrophils. This study is a description of the crucial role of cording in the in vivo physiopathology ofM. abscessusinfection and emphasizes cording as a mechanism of immune evasion.

scholarly journals On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition?

1978 ◽  
Vol 147 (3) ◽  
pp. 882-896 ◽  
Author(s):  
R M Zinkernagel ◽  
G N Callahan ◽  
A Althage ◽  
S Cooper ◽  
P A Klein ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cytotoxic T Cells ◽  
Thymic Epithelial Cells ◽  
Self Recognition ◽  
Specific Cytotoxicity ◽  
Restricted Activity ◽  
Bone Marrow Chimeras ◽  
Killer T Cells

In the thymus, precursor T cells differentiate recognition structures for self that are specific for the H-2K, D, and I markers expressed by the thymic epithelium. Thus recognition of self-H-2 differentiates independently of the T cells H-2 type and independently of recognition of nonself antigen X. This is readily compatible with dual recognition by T cells but does not formally exclude a single recognition model. These conclusions derive from experiments with bone marrow and thymic chimeras. Irradiated mice reconstituted with bone marrow to form chimeras of (A X B)F1 leads to A type generate virus-specific cytotoxic T cells for infected targets A only. Therefore, the H-2 type of the host determines the H-2-restricted activity of killer T cells alone. In contrast, chimeras made by reconstituting irradiated A mice with adult spleen cells of (A X B)F1 origin generate virus-specific cytotoxic activity for infected A and B targets, suggesting that mature T cells do not change their self-specificity readily. (A X B)F1 leads to (A X C)F1 and (KAIA/DC) leads to (KAIA/DB) irradiation bone marrow chimeras responded against infected A but not B or C targets. This suggests that cytotoxicity is not generated against DC because it is abscent from the host's thymus epithelium and not against DB because it is not expressed by the reconstituting lymphoreticular system. (KBIB/DA) leads to (KCIC/DA) K, I incompatible, or completely H-2 incompatible A leads to B chimeras fail to generate any measurable virus specific cytotoxicity, indicating the necessity for I-specific helper T cells for the generation of killer T cells. Finally adult thymectomized, irradiated and bone marrow reconstituted (A X B)F1 mice, transplanted with an irradiated thymus of A origin, generate virus-specific cytotoxic T cells specific for infected A targets but not for B targets; this result formally demonstrates the crucial role of thymic epithelial cells in the differentiation of anti-self-H-2 specificities of T cells.

scholarly journals Role of MiR-98 and Its Underlying Mechanisms in Systemic Lupus Erythematosus

2018 ◽  
Vol 45 (10) ◽  
pp. 1397-1405 ◽  
Author(s):  
Lin Xie ◽  
Jinhua Xu
Keyword(s):  
T Cells ◽  
Lupus Erythematosus ◽  
Cd4 T Cells ◽  
Opposite Effect ◽  
Luciferase Reporter ◽  
Qrt Pcr ◽  
Fas Mrna ◽  
Reporter Assays ◽  
Underlying Mechanisms

Objective.T-lymphocyte apoptosis plays a critical role in the pathogenesis of systemic lupus erythematosus (SLE). However, the underlying regulatory mechanisms of apoptosis in SLE remain unclear. The aim of this study was to explore the role of miR-98 in SLE and its underlying mechanisms.Methods.Western blotting and quantitative reverse transcription PCR (qRT-PCR) were used to analyze miR-98 and Fas expression. Luciferase reporter assays were performed to identify miR-98 targets. To modify miRNA levels, miR-98 mimics and inhibitor were transfected into cells. A lentiviral construct was used to overexpress the level of Fas in SLE CD4+ T cells. Gene and protein expression were determined by qRT-PCR and Western blotting. Apoptosis levels were evaluated by annexin V staining and flow cytometry.Results.Compared to those of healthy donors, miR-98 was downregulated in SLE CD4+ T cells, whereas Fas mRNA and protein expression were upregulated. Upregulation of miR-98 by mimic transfection protected Jurkat cells against Fas-mediated apoptosis at both mRNA and protein levels, while miR-98 inhibitor induced the completely opposite effect. Luciferase reporter assays demonstrated that miR-98 directly targeted Fas mRNA. Further, miR-98 inhibitor induced apoptosis in primary healthy CD4+ T cells through the Fas-caspase axis, while upregulation of miR-98 in SLE CD4+ T cells led to the opposite effect.Conclusion.The current study revealed that downregulation of miR-98 induces apoptosis by modulating the Fas-mediated apoptotic signaling pathway in SLE CD4+ T cells. These results suggest that miR-98 might serve as a potential target for SLE treatment.

scholarly journals TLR3 Serves as a Prognostic Biomarker and Associates with Immune Infiltration in the Renal Clear Cell Carcinoma Microenvironment

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Guodong Liao ◽  
Jia Lv ◽  
Alin Ji ◽  
Shuai Meng ◽  
Chao Chen
Keyword(s):  
T Cells ◽  
Clear Cell ◽  
Prognostic Biomarker ◽  
Positive Association ◽  
Renal Clear Cell Carcinoma ◽  
Signalling Pathway ◽  
Poor Overall Survival ◽  
Immune Infiltration ◽  
Tlr3 Expression

Background. Clear cell renal cancer (KIRC) is one of the most common cancers globally, with a poor prognosis. TLRs play a vital role in anticancer immunity and the regulation of the biological progress of tumour cells. However, the precise role of TLRs in KIRC is still ambiguous. Methods. Various bioinformatics analysis and clinical validation of tissues were performed to evaluate the prognostic value of TLRs and their correlation with immune infiltration in KIRC. Results. The expression of TLR2/3/7/8 was increased at both mRNA and protein levels in KIRC. TLRs in KIRC were involved in the activation of apoptosis, EMT, RAS/MAPK, and RTK pathways, as well as the inhibition of the cell cycle and the hormone AR pathway. Drug sensitivity analysis revealed that high expression of TLR3 and low expression of TLR7/9/10 were resistant to most of the small molecules or drugs from CTRP. Enrichment analyses showed that TLRs were mainly involved in innate immune response, toll-like receptor signalling pathway, NF-kappa B signalling pathway, and TNF signalling pathway. Furthermore, a high-level TLR3 expression was associated with a favourable prognosis in KIRC. Validation research further confirmed that TLR3 expression was increased in KIRC tissues, and high TLR3 levels were associated with poor overall survival. Moreover, TLR3 in KIRC showed a positive association with an abundance of immune cells, including B-cells, CD4+ T-cells, CD8+ T-cells, macrophage, neutrophils, and dendritic cells, and the expression of the immune biomarker sets. Several TLR3-associated kinase, miRNA, or transcription factor targets were also identified in KIRC. Conclusion. Our results indicate that TLR3 serves as a prognostic biomarker and associated with immune infiltration in KIRC. This work lays a foundation for further studies on the role of TLR3 in the carcinogenesis and progression of KIRC.

scholarly journals Therapeutic Implications of Targeting Heat Shock Protein 70 by Immunization or Antibodies in Experimental Skin Inflammation

2021 ◽  
Vol 12 ◽  
Author(s):  
Stefan Tukaj ◽  
Jagoda Mantej ◽  
Michał Sobala ◽  
Katarzyna Potrykus ◽  
Zbigniew Tukaj ◽  
...  
Keyword(s):  
T Cells ◽  
Heat Shock ◽  
Skin Inflammation ◽  
Antibody Treatment ◽  
Therapeutic Implications ◽  
Promising Therapeutic Target ◽  
Shock Proteins ◽  
Autoimmune Dermatoses

Heat shock proteins (Hsp) are constitutive and stress-induced molecules which have been reported to impact innate and adaptive immune responses. Here, we evaluated the role of Hsp70 as a treatment target in the imiquimod-induced, psoriasis-like skin inflammation mouse model and related in vitro assays. We found that immunization of mice with Hsp70 resulted in decreased clinical and histological disease severity associated with expansion of T cells in favor of regulatory subtypes (CD4+FoxP3+/CD4+CD25+ cells). Similarly, anti-Hsp70 antibody treatment led to lowered disease activity associated with down-regulation of pro-inflammatory Th17 cells. A direct stimulating action of Hsp70 on regulatory T cells and its anti-proliferative effects on keratinocytes were confirmed in cell culture experiments. Our observations suggest that Hsp70 may be a promising therapeutic target in psoriasis and potentially other autoimmune dermatoses.

scholarly journals Increased regulatory B cells are involved in immune evasion in patients with gastric cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yuki Murakami ◽  
Hiroaki Saito ◽  
Shota Shimizu ◽  
Yusuke Kono ◽  
Yuji Shishido ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
B Cells ◽  
Immune Evasion ◽  
Survival Rates ◽  
Prognostic Indicator ◽  
Interleukin 10 ◽  
Regulatory B Cells ◽  
Carboxyfluorescein Succinimidyl Ester

Abstract Accumulating evidence has indicated that immune regulatory cells are involved in the establishment of tumoral immune evasion. However, the role of regulatory B cells (Bregs) in this remains unclear. Here, we identified a role for Bregs in immune evasion in gastric cancer (GC) patients. The frequency of peripheral Bregs was significantly higher in GC patients than in healthy controls (P = 0.0023). Moreover, the frequency of CD19+CD24hiCD27+ B cells in GC tissue was significantly higher than in peripheral blood and healthy gastric tissue. Carboxyfluorescein succinimidyl ester labeling revealed that CD19+CD24hiCD27+ B cells could suppress the proliferation of autologous CD4+ T cells. Moreover, CD19+CD24hiCD27+ B cells inhibited the production of interferon-gamma by CD4+ T cells. Double staining immunohistochemistry of interleukin-10 and CD19 revealed 5-year overall survival rates of 65.4% and 13.3% in BregLow and BregHigh groups, respectively (P < 0.0001). Multivariate analysis indicated that the frequency of Bregs was an independent prognostic indicator in GC patients. Taken together, our results show the existence of Bregs in GC tissue, and indicate that they are significantly correlated with the prognosis of GC patients.

Role of IP-10/CXCL10 in the progression of pancreatitis-like injury in mice after murine retroviral infection

2006 ◽  
Vol 291 (2) ◽  
pp. G345-G354 ◽  
Author(s):  
Yusuke Kawauchi ◽  
Kenji Suzuki ◽  
Shiro Watanabe ◽  
Satoshi Yamagiwa ◽  
Hiroyuki Yoneyama ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Leukemia Virus ◽  
Mesenteric Lymph Nodes ◽  
T Helper 1 ◽  
Antibody Treatment ◽  
Retroviral Infection ◽  
Ifn Γ ◽  
Inducible Protein

Exocrinopathy and pancreatitis-like injury were developed in C57BL/6 (B6) mice infected with LP-BM5 murine leukemia virus, which is known to induce murine acquired immunodeficiency syndrome (MAIDS). The role of chemokines, especially CXCL10/interferon (IFN)-γ-inducible protein 10 (IP-10), a chemokine to attract CXCR3+T helper 1-type CD4+T cells, has not been investigated thoroughly in the pathogenesis of pancreatitis. B6 mice were inoculated intraperitoneally with LP-BM5 and then injected every week with either an antibody against IP-10 or a control antibody. Eight weeks after infection, we analyzed the effect of IP-10 neutralization. Anti-IP-10 antibody treatment did not change the generalized lymphadenopathy and hepatosplenomegaly of mice with MAIDS. The treatment significantly reduced the number of IP-10- and CXCR3-positive cells in the mesenteric lymph nodes (mLNs) but not the phenotypes and gross numbers of cells. In contrast, IP-10 neutralization reduced the number of mononuclear cells infiltrating into the pancreas. Anti-IP-10 antibody treatment did not change the numbers of IFN-γ+and IL10+cells in the mLN but significantly reduced their numbers, especially IFN-γ+and IL-10+CD4+T cells and IFN-γ+Mac-1+cells, in the pancreas. IP-10 neutralization ameliorated the pancreatic lesions of mice with MAIDS probably by blocking the cellular infiltration of CD4+T cells and IFN-γ+Mac-1+cells into the pancreas at least at 8 wk after infection, suggesting that IP-10 and these cells might play a key role in the development of chronic autoimmune pancreatitis.

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