Abstract 4303: Heme Oxygenase 1 Expression in Dendritic Cells Drives Cd4+ T Cell Activation in Transplantation Atherosclerosis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Annemarie M Noordeloos ◽  
C Cheng ◽  
E van Deel ◽  
D Tempel ◽  
M L Simoons ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Heme Oxygenase 1 ◽  
Cell Ratio ◽  
Mhc Ii ◽  
T Cell Infiltration ◽  
T Cell Priming

Although over-expression of heme oxygenase-1 (HO-1) attenuates transplantation arteriosclerosis, the mechanism by which HO-1 exerts its protective effect remains unclear. In order to investigate the effect of HO-1 expression specifically in the dendritic cell (DC) in the context of transplantation atherosclerosis, we studied the effect of HO1-deficient versus wildtype (WT) DCs on the T-cell priming response and outcome in a murine transplant arteriosclerosis model. At day 0 C57bl6 mice received either WT (N=7) or HO1-knockout DCs (N=7) pre-sensitized with Balb/c splenocytes lysate. At day 10 an allogenic aorta segment derived from Balb/c mice was transplanted into the carotid artery position of C57Bl6 mice. 14 days post transplantation, the grafts were harvested and analyzed by imumnohistology. Adoptive transfer of HO1-deficient DCs significantly increased neointimal hyperplasia as compared to WT DCs (116995 versus 38428 μm2 P<0.05). HO-1 deficient DCs also increased medial thickeness (15936 versus 12034 μm2 P<0.05), reduced intimal VSMCs content (46 versus 75% P<0.05) and resulted in more prominent medial cell infiltration (461 versus 232 μm2 P<0.05). In the transplanted aorta of the with HO-1 nullizygous DCs treated recipient group, an increase in CD4+ T-cell infiltration (9.5 versus 0.2% in WT P<0.05) and IgG deposition, concomitant to a decrease of CD8+ T cell infiltration (8.1 versus 14.3%, P<0.05) was observed. In line with these observations, in vitro analysis of HO-1 deficiency in DC function showed an increased priming potential for CD4+ T cells, thereby increasing the CD4+/CD8+ T cell ratio. Increased efficiency in CD4+ T cell priming by HO-1 deficient DCs was facilitated by a higher cell surface level of MHC II. Further studies indicated that HO-1 deficiency increased STAT1 phosphorylation, thereby enhancing CIITA gene expression that lead to increased MHC II levels on the DCs cell surface. HO-1 deficiency in dendritic cells increases vascular cell infiltration with a higher CD4+/CD8 T-cell ratio in vascular allografts resulting in an augmented form of transplantation arteriosclerosis. This effect is facilitated by a STAT1-CIITA-MHCII dependent intracellular pathway.

Abstract 760: Heme Oxygenase-1 expression in Dendritic Cells determines the Outcome of Transplantation Arteriosclerosis

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Annemarie Noordeloos ◽  
Elza van Deel ◽  
Denise Hermes ◽  
Maarten L Simoons ◽  
Dirk J Duncker ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Heme Oxygenase ◽  
T Cell Activation ◽  
Neointimal Hyperplasia ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Heme Oxygenase 1 ◽  
T Cell Infiltration ◽  
Mhcii Expression

Introduction: Although expression of heme oxygenase-1 (HO1) attenuates transplantation arteriosclerosis, the mechanism by which HO1 exerts its protective effect remains unclear. We studied the effect of HO1-deficient vs. wildtype (WT) dendritic cells (DCs) on the T-cell priming response and outcome in a murine transplant arteriosclerosis model. Methods: At day 0 C57bl6 mice received either WT (n=6) or HO1-knockout DCs (n=6) pre-sensitized with Balb/c splenocytes lysate to accelerate the development of arteriosclerosis. At day 10 an aorta segment from Balb/c mice was transplanted into the carotid artery position of C57Bl6 mice.14 days after transplantation allografts were excised and processed for immunohistochemical analysis. Results: HO1-deficient DCs significantly increased neointimal hyperplasia as compared to WT DCs (116995 vs. 46114μm 2 P<0.05) and incidence of intima formation (83 vs. 50% in WT DC). HO1 deficient DCs also increased medial thickeness (15936 vs.12034 μm 2 P<0.05) and intimal VSMCs content (76 vs. 46% P<0.05) and resulted in more prominent medial cell infiltration (461μm 2 vs. 232μm 2 P<0.05). Although HO1 deficient and WT DCs could be detected in allografts, HO1-nullizygous DCs induced an increase in CD4+ T-cell infiltration (9.5 vs. 0.1% in WT P<0.05) concomitant to a decrease of CD8+ T cell infiltration (8 vs.14%, P<0.05). In line with these observations Affymetrix microarray analysis confirmed that HO1 deletion in DCs was associated with a significant downregulation of MHCII-H2A expression (associated with CD4+T-cell activation) and induction of inhibitors of MHCII expression (including IK protein) whereas MHC I expression remained unchanged. Conclusions: HO1 expression in dendritic cells increases vascular cell infiltration with a higher CD8+/CD4+ T-cell ratio by stabilizing MHCII expression in vascular allografts resulting in inhibition of neointima formation and hence improved allograft survival.

scholarly journals Major Histocompatibility Complex Class II Expression by Intrinsic Renal Cells Is Required for Crescentic Glomerulonephritis

1998 ◽  
Vol 188 (3) ◽  
pp. 597-602 ◽  
Author(s):  
Shuo Li ◽  
Christian Kurts ◽  
Frank Köntgen ◽  
Stephen R. Holdsworth ◽  
Peter G. Tipping
Keyword(s):  
T Cell ◽  
Renal Injury ◽  
Crescentic Glomerulonephritis ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Renal Cells ◽  
Chimeric Mice ◽  
Mhc Ii ◽  
T Cell Infiltration ◽  
Histocompatibility Complex

The requirement for major histocompatibility complex class II (MHC II) to initiate immune renal injury was studied in a murine model of CD4+ T cell–dependent crescentic glomerulonephritis (GN). C57BL/6 (MHC II+/+) mice developed crescentic GN with glomerular CD4+ T cell infiltration and renal injury, in response to a nephritogenic antigen (sheep globulin) planted on their glomerular basement membrane. MHC II–deficient C57BL/6 mice (MHC II−/−) did not develop crescentic GN, CD4+ T cell infiltration, or injury, indicating that this form of immune glomerular injury is MHC II dependent. The requirement for MHC II expression by intrinsic renal cells was studied in chimeric mice, which expressed MHC II on bone marrow–derived cells and in the thymus, but not in the kidneys. These chimeric mice had normal T and B cell populations and MHC II expression in their spleens and lymph nodes and developed an immune response to systemically and cutaneously administered sheep globulin. However, they did not develop crescentic GN, CD4+ T cell infiltration, or renal injury in response to the sheep globulin planted in their glomeruli. These studies demonstrate that interaction of CD4+ T cells with intrinsic renal cells expressing MHC II is required for development of cell-mediated immune renal injury.

Overexpression of LILRB2 (ILT4) is correlated with immunosuppressive immune infiltration in lung adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20519-e20519
Author(s):  
Butuo Li ◽  
Chao Jiang ◽  
Shijiang Wang ◽  
Xuanzong Li ◽  
Yiyue Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Lung Adenocarcinoma ◽  
Objective Response ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
M2 Macrophage ◽  
Immune Infiltration ◽  
T Cell Infiltration ◽  
The Relationship

e20519 Background: Immune checkpoint inhibitors have revolutionized the patterns of tumor treatment with significantly improved survival. However, it’s worth noting that the objective response rate of PD-1/PD-L1 inhibitors monotherapy is just 20% in non-small cell lung cancer (NSCLC) patients, and biomarkers for the prognosis of patients receiving PD-1/PD-L1 inhibitors are urgently needed. LILRB2 (ILT4) is known as an immunosuppressive molecule and promotes the development and progression of NSCLC. However, the relationship between LILRB2 expression and immune microenvironment remains unclear in patients with lung adenocarcinoma. Methods: Expression profile and corresponding clinicopathological data of patients with lung adenocarcinoma were obtained from The Cancer Genome Atlas (TCGA) database. TIMER 2.0 was used to investigate the relationship between LILRB2 expression and immune infiltrates, including T cell subset, macrophage and so on. Cox proportional hazard model was also performed to evaluate the role LILRB2 expression and immune infiltrations in prognostic prediction of patients with lung adenocarcinoma. Results: 515 patients with lung adenocarcinoma were included in analysis from TCGA dataset. LILRB2 expression was found to have significant negative correlation with CD8+ T cell infiltration (P = 0.0012), and positive correlation with CD4+ T cell infiltration (P < 0.001). There were also significant positive correlations between LILRB2 expression and Treg (P = 0.0083), cancer associated fibroblast (P < 0.001), monocyte (P < 0.001), M2 macrophage (P < 0.001) infiltration, which was regarded as the marker of immunosuppressive microenvironment. Notably, there were also significant association between the expression of LILRB2 and PD-1 (P < 0.001) and PD-L1(P < 0.001). In terms of survival analysis, high level of Treg (HR = 0.86, P = 0.03) and M2 macrophage (HR = 0.84, P = 0.017) infiltration was associated with poor prognosis of patients with lung adenocarcinoma. However, the level of CD8+T cell (HR = 0.93, P = 0.298), CD4+ T cell (HR = 0.933, P = 0.321), and LILRB2 expression (P = 0.56) was not associated with the survival of patient with lung adenocarcinoma. Conclusions: The overexpression of LILRB2 is significantly correlated with immunosuppressive immune infiltration and microenvironment in lung adenocarcinoma and might be the potential predictive biomarkers for the PD-1/PD-L1 inhibitors.

scholarly journals m6A Modification Patterns Identify a Subset of Follicular Lymphoma Harboring an Exhausted Tumor Microenvironment

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4486-4486
Author(s):  
Xianhuo Wang ◽  
Tingting Zhang ◽  
Hengqi Liu ◽  
Sicong Zhang ◽  
Kai Fu ◽  
...  
Keyword(s):  
T Cell ◽  
Follicular Lymphoma ◽  
Cd8 T Cell ◽  
Gene Signature ◽  
Cd4 T Cell ◽  
Cell Infiltration ◽  
Biological Processes ◽  
T Cell Infiltration ◽  
Cluster A

Abstract Background: Epigenetic dysregulation is important for the pathogenesis of follicular lymphoma (FL). N6-methyladenosine (m6A) is the most common post-transcriptional modification of mRNA. The m6A modification affects a wide range of cellular processes, including RNA stability, export, splicing or translation, and is extensively involved in the development and progression of multiple non-hematological and hematological malignancies. However, the role of m6A modification in FL remain largely unknown. Methods: We comprehensively evaluated the m6A modification patterns of 351 FL patients from three cohorts based on 16 m6A regulators and constructed the m6A gene signature the by unsupervised clustering analysis. The m6A score was then established using principal component analysis. The association between m6A modification patterns and prognostic implications, biological processes, and microenvironment characterizations in FL were further investigated. Results: A total of 16 m6A regulators were finally identified in this study, including 8 writers, 7 readers and one eraser. Two distinct m6A modification patterns, termed as m6A cluster A and m6A cluster B respectively, were identified based on the similarity displayed by the expression levels of 16 m6A regulators and the proportion of ambiguous clustering measure. Patients with m6A cluster A had significantly poorer survival than those with m6A cluster B (p=0.0085) and showed enrichment in cell cycle, DNA replication and mismatch repair biological processes. However, patients with m6A cluster B were markedly enriched in MAPK pathway, WNT pathway, mTOR pathway, natural killer cell mediated cototoxicity, cytokine-cytokine receptor interaction and T-cell receptor pathway. Additionally, myeloid dendritic cell and CD8 + T cell were significantly enriched in m6A cluster A, nevertheless CD4 + T cell was abundant in m6A cluster B. Base on the DEGs between m6A cluster A and m6A cluster B, a m6A gene signature was further constructed, namely m6A gene signature A and m6A gene signature B. Patients with m6A gene signature B experienced worse outcome than those with m6A gene signature A. Simultaneously, a m6A scoring model was also established to quantify the m6A modification pattern of individual patients with FL. Patients with low m6A score presented a prominent inferior survival than those with high m6A score (p&lt; 0.0001). The median survival times for patients with low and high m6A score were 8.84 (95% confidence interval [CI]: 7.251-10.429) and 15.73 years (95% CI: 11.729-19.731), respectively. High m6A score group was remarkably riched in macrophage cell and CD4 + T cell infiltration, while low m6A score group exhibited significantly increased myeloid dendritic cell and CD8 + T cell infiltration, suggesting that m6A score could distinguish populations with distinct immune cell infiltration characteristics. GSVA analysis showed that the expression of genes involved in the immune and inflammatory response was significantly upregulated in low m6A score group. But we finally found that the CD8 + T cells in low m6A score group kept in a state of exhaustion, leading to that exhausted T cells were enriched in low m6A score group. The expression of PD-1 and PD-L1 in low m6A score group was also higher than those in high m6A score group. GSEA analysis showed that low m6A score group exhibited an enhanced IFN-γ response. Finally, we verified the value of the m6A score for predicting response to anti-PD-L1 antibody in external immunotherapy cohort (IMvigor210), and found that patients with low m6A score exhibited significantly clinical benefits and a markedly prolonged survival from anti-PD-L1 therapy. Conclusions: This is the first time to comprehensively investigate the role of m6A modification in FL. The m6A score identifies a subset of follicular lymphoma harboring an exhausted tumor microenvironment and helps for the selection of patients for immunotherapy, guiding the personalized immunotherapy in FL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals PD‐L1+ dendritic cells in the tumor microenvironment correlate with good prognosis and CD8+ T cell infiltration in colon cancer

2020 ◽  
Author(s):  
Timothy J Miller ◽  
Chidozie C Anyaegbu ◽  
Tracey F Lee‐Pullen ◽  
Lisa J Spalding ◽  
Cameron F Platell ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Dendritic Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cell ◽  
Good Prognosis ◽  
Cell Infiltration ◽  
T Cell Infiltration

scholarly journals Modelling the interplay between the CD4$$^{+}$$/CD8$$^{+}$$ T-cell ratio and the expression of MHC-I in tumours

2021 ◽  
Vol 83 (1) ◽  
Author(s):  
Christian John Hurry ◽  
Alexander Mozeika ◽  
Alessia Annibale
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Critical Level ◽  
Cell Infiltration ◽  
Cytotoxic T Cell ◽  
Mhc I ◽  
Cell Ratio ◽  
T Cell Infiltration ◽  
Immunological Mechanisms ◽  
Tcr Repertoire

AbstractDescribing the anti-tumour immune response as a series of cellular kinetic reactions from known immunological mechanisms, we create a mathematical model that shows the CD4$$^{+}$$ + /CD8$$^{+}$$ + T-cell ratio, T-cell infiltration and the expression of MHC-I to be interacting factors in tumour elimination. Methods from dynamical systems theory and non-equilibrium statistical mechanics are used to model the T-cell dependent anti-tumour immune response. Our model predicts a critical level of MHC-I expression which determines whether or not the tumour escapes the immune response. This critical level of MHC-I depends on the helper/cytotoxic T-cell ratio. However, our model also suggests that the immune system is robust against small changes in this ratio. We also find that T-cell infiltration and the specificity of the intra-tumour TCR repertoire will affect the critical MHC-I expression. Our work suggests that the functional form of the time evolution of MHC-I expression may explain the qualitative behaviour of tumour growth seen in patients.

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