scholarly journals Direct CD137 costimulation of CD8 T cells promotes retention and innate-like function within nascent atherogenic foci

2019 ◽  
Vol 316 (6) ◽  
pp. H1480-H1494 ◽  
Author(s):  
Maria M. Xu ◽  
Antoine Ménoret ◽  
Sarah-Anne E. Nicholas ◽  
Sebastian Günther ◽  
Eric J. Sundberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Antigen Recognition ◽  
Cell Infiltration ◽  
Antigen Specificity ◽  
Effector Cells ◽  
T Cell Infiltration

Effector CD8 T cells infiltrate atherosclerotic lesions and are correlated with cardiovascular events, but the mechanisms regulating their recruitment and retention are not well understood. CD137 (4–1BB) is a costimulatory receptor induced on immune cells and expressed at sites of human atherosclerotic plaque. Genetic variants associated with decreased CD137 expression correlate with carotid-intimal thickness and its deficiency in animal models attenuates atherosclerosis. These effects have been attributed in part to endothelial responses to low and disturbed flow (LDF), but CD137 also generates robust effector CD8 T cells as a costimulatory signal. Thus, we asked whether CD8 T cell-specific CD137 stimulation contributes to their infiltration, retention, and IFNγ production in early atherogenesis. We tested this through adoptive transfer of CD8 T cells into recipient C57BL/6J mice that were then antigen primed and CD137 costimulated. We analyzed atherogenic LDF vessels in normolipidemic and PCSK9-mediated hyperlipidemic models and utilized a digestion protocol that allowed for lesional T-cell characterization via flow cytometry and in vitro stimulation. We found that CD137 activation, specifically of effector CD8 T cells, triggers their intimal infiltration into LDF vessels and promotes a persistent innate-like proinflammatory program. Residence of CD137+ effector CD8 T cells further promoted infiltration of endogenous CD8 T cells with IFNγ-producing potential, whereas CD137-deficient CD8 T cells exhibited impaired vessel infiltration, minimal IFNγ production, and reduced infiltration of endogenous CD8 T cells. Our studies thus provide novel insight into how CD137 costimulation of effector T cells, independent of plaque-antigen recognition, instigates their retention and promotes innate-like responses from immune infiltrates within atherogenic foci. NEW & NOTEWORTHY Our studies identify CD137 costimulation as a stimulus for effector CD8 T-cell infiltration and persistence within atherogenic foci, regardless of atherosclerotic-antigen recognition. These costimulated effector cells, which are generated in pathological states such as viral infection and autoimmunity, have innate-like proinflammatory programs in circulation and within the atherosclerotic microenvironment, providing mechanistic context for clinical correlations of cardiovascular morbidity with increased CD8 T-cell infiltration and markers of activation in the absence of established antigen specificity. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/effector-cd8-t-cells-seed-atherogenic-foci/ .

Immunogenomic classification of gastric cancer based on the tumor microenvironments expression of PD-L1 and CD8+ T-cell infiltration.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16578-e16578
Author(s):  
Yu Chen ◽  
Gang Chen ◽  
Jia-ni Xiong ◽  
Bin Lan ◽  
Xuan Gao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Type I ◽  
T Cell Infiltration ◽  
Genetic Features

e16578 Background: Previous data has shown that a positive response to immunotherapy usually relies on active interactions between tumor cells and immunomodulators inside the tumor microenvironment (TME). The aim of this study was to classify gastric cancer (GC) subsets based on the TME immune status according to the expression of PD-L1 and infiltration of CD8+ T cells. Methods: One hundred and eighty-six tumor tissue from gastric cancer patients with a curative D2 gastrectomy were examined for evaluating PD-L1 and CD8+ T cells status using histopathologic analysis. The molecular characteristics of 289 GC samples in TCGA network were further analyzed to distinguish the genetic features of four immune subtypes depending on the presence of PD-L1/CD8+T cell. Results: GC samples were categorized into four types, type I (CD8+/PD-L1+, 60.3%), II (CD8-/PD-L1-, 11.8%), III (CD8-/PD-L1+, 0%), and IV (CD8+/PD-L1-, 27.9%), basing on PD-L1/CD8 expression. The PD-L1 expressing level was geographically associated with the intensity of CD8+ T cell infiltration which was significantly associated with disease-free survival (DFS) and overall survival (OS) (p = 0.003 and p = 0.006). Distinct patterns of genetic profile were described in four types of GC from TCGA database. Type I and III which PD-L1 were overly expressed had comparatively higher MSI and TMB, with EBV mainly enriched in Type I, whereas CIN was more likely to occur in PD-L1 aberrant types II and IV. SNV analysis illustrated higher gene mutations in oncogenes (PIK3CA and ERBB2), and in DNA damage repair related pathway, such as PRKDC, ATM, and SWI/SNF complexes (e.g. ARID1A) in Type I. However, TP53 mutations tend to enrich in Type II and IV. Similar results were obtained by transcriptome analysis. Conclusions: The genetic features of four immune subtypes proof that PD-L1 and CD8+ T cells status are reasonable immunogenomic classification of gastric cancer. SNV analysis prompts a potential mechanism for effectiveness of immunotherapy in Type I patients. Overall, the results may be useful for the development of clinical treatments for the blockade of immune checkpoints.

scholarly journals IL-4 sensitivity shapes the peripheral CD8+ T cell pool and response to infection

2016 ◽  
Vol 213 (7) ◽  
pp. 1319-1329 ◽  
Author(s):  
Kristin R. Renkema ◽  
June-Yong Lee ◽  
You Jeong Lee ◽  
Sara E. Hamilton ◽  
Kristin A. Hogquist ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Antigen Specificity ◽  
Th1 Cell ◽  
Memory Cd8 T Cells ◽  
Expression Levels ◽  
Cell Pool

Previous studies have revealed that a population of innate memory CD8+ T cells is generated in response to IL-4, first appearing in the thymus and bearing high expression levels of Eomesodermin (Eomes) but not T-bet. However, the antigen specificity and functional properties of these cells is poorly defined. In this study, we show that IL-4 regulates not only the frequency and function of innate memory CD8+ T cells, but also regulates Eomes expression levels and functional reactivity of naive CD8+ T cells. Lack of IL-4 responsiveness attenuates the capacity of CD8+ T cells to mount a robust response to lymphocytic choriomeningitis virus infection, with both quantitative and qualitative effects on effector and memory antigen-specific CD8+ T cells. Unexpectedly, we found that, although numerically rare, memory phenotype CD8+ T cells in IL-4Rα–deficient mice exhibited enhanced reactivity after in vitro and in vivo stimulation. Importantly, our data revealed that these effects of IL-4 exposure occur before, not during, infection. Together, these data show that IL-4 influences the entire peripheral CD8+ T cell pool, influencing expression of T-box transcription factors, functional reactivity, and the capacity to respond to infection. These findings indicate that IL-4, a canonical Th2 cell cytokine, can sometimes promote rather than impair Th1 cell–type immune responses.

scholarly journals CD73 Ectonucleotidase Restrains CD8+ T Cell Metabolic Fitness and Anti-tumoral Activity

2021 ◽  
Vol 9 ◽  
Author(s):  
Pedro Briceño ◽  
Elizabeth Rivas-Yañez ◽  
Mariana V. Rosemblatt ◽  
Brian Parra-Tello ◽  
Paula Farías ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Cd8 T Cell ◽  
Tumor Burden ◽  
Effector Cells ◽  
Cd73 Expression ◽  
Metabolic Fitness

CD39 and CD73 are ectoenzymes that dephosphorylate ATP into its metabolites; ADP, AMP, and adenosine, and thus are considered instrumental in the development of immunosuppressive microenvironments. We have previously shown that within the CD8+ T cell population, naïve and memory cells express the CD73 ectonucleotidase, while terminally differentiated effector cells are devoid of this enzyme. This evidence suggests that adenosine might exert an autocrine effect on CD8+ T cells during T cell differentiation. To study the possible role of CD73 and adenosine during this process, we compared the expression of the adenosinergic signaling components, the phenotype, and the functional properties between CD73-deficient and WT CD8+ T cells. Upon activation, we observed an upregulation of CD73 expression in CD8+ T cells along with an upregulation of the adenosine A2A receptor. Interestingly, when we differentiated CD8+ T cells to Tc1 cells in vitro, we observed that these cells produce adenosine and that CD73-deficient cells present a higher cytotoxic potential evidenced by an increase in IFN-γ, TNF-α, and granzyme B production. Moreover, CD73-deficient cells presented a increased glucose uptake and higher mitochondrial respiration, indicating that this ectonucleotidase restrict the mitochondrial capacity in CD8+ T cells. In agreement, when adoptively transferred, antigen-specific CD73-deficient CD8+ T cells were more effective in reducing the tumor burden in B16.OVA melanoma-bearing mice and presented lower levels of exhaustion markers than wild type cells. All these data suggest an autocrine effect of CD73-mediated adenosine production, limiting differentiation and cytotoxic T cells’ metabolic fitness.

scholarly journals Identification of Key Genes Related to CD8+ T-Cell Infiltration as Prognostic Biomarkers for Lung Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Minjun Du ◽  
Yicheng Liang ◽  
Zixu Liu ◽  
Xingkai Li ◽  
Mei Liang ◽  
...  
Keyword(s):  
Risk Assessment ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Assessment Model ◽  
Cell Infiltration ◽  
Risk Assessment Model ◽  
T Cell Infiltration ◽  
Key Genes

BackgroundCD8+ T cells are one of the central effector cells in the immune microenvironment. CD8+ T cells play a vital role in the development and progression of lung adenocarcinoma (LUAD). This study aimed to explore the key genes related to CD8+ T-cell infiltration in LUAD and to develop a novel prognosis model based on these genes.MethodsWith the use of the LUAD dataset from The Cancer Genome Atlas (TCGA), the differentially expressed genes (DEGs) were analyzed, and a co-expression network was constructed by weighted gene co-expression network analysis (WGCNA). Combined with the CIBERSORT algorithm, the gene module in WGCNA, which was the most significantly correlated with CD8+ T cells, was selected for the subsequent analyses. Key genes were then identified by co-expression network analysis, protein–protein interactions network analysis, and least absolute shrinkage and selection operator (Lasso)-penalized Cox regression analysis. A risk assessment model was built based on these key genes and then validated by the dataset from the Gene Expression Omnibus (GEO) database and multiple fluorescence in situ hybridization experiments of a tissue microarray.ResultsFive key genes (MZT2A, ALG3, ATIC, GPI, and GAPDH) related to prognosis and CD8+ T-cell infiltration were identified, and a risk assessment model was established based on them. We found that the risk score could well predict the prognosis of LUAD, and the risk score was negatively related to CD8+ T-cell infiltration and correlated with the advanced tumor stage. The results of the GEO database and tissue microarray were consistent with those of TCGA. Furthermore, the risk score was higher significantly in tumor tissues than in adjacent lung tissues and was correlated with the advanced tumor stage.ConclusionsThis study may provide a novel risk assessment model for prognosis prediction and a new perspective to explore the mechanism of tumor immune microenvironment related to CD8+ T-cell infiltration in LUAD.

scholarly journals IL-15 induces antigen-independent expansion and differentiation of human naive CD8+ T cells in vitro

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2541-2546 ◽  
Author(s):  
Nuno L. Alves ◽  
Berend Hooibrink ◽  
Fernando A. Arosa ◽  
René A. W. van Lier
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Interferon Γ ◽  
T Cell Subsets ◽  
Memory Cd8 T Cells ◽  
Effector Cells ◽  
Independent Expansion

Abstract Recent studies in mice have shown that although interleukin 15 (IL-15) plays an important role in regulating homeostasis of memory CD8+ T cells, it has no apparent function in controlling homeostatic proliferation of naive T cells. We here assessed the influence of IL-15 on antigen-independent expansion and differentiation of human CD8+ T cells. Both naive and primed human T cells divided in response to IL-15. In this process, naive CD8+ T cells successively down-regulated CD45RA and CD28 but maintained CD27 expression. Concomitant with these phenotypic changes, naive cells acquired the ability to produce interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α), expressed perforin and granzyme B, and acquired cytotoxic properties. Primed CD8+ T cells, from both noncytotoxic (CD45RA-CD27+) and cytotoxic (CD45RA+CD27-) subsets, responded to IL-15 and yielded ample numbers of cytokine-secreting and cytotoxic effector cells. In summary, all human CD8+ T-cell subsets had the ability to respond to IL-15, which suggests a generic influence of this cytokine on CD8+ T-cell homeostasis in man. (Blood. 2003;102:2541-2546)

scholarly journals Global pattern of CD8+ T cell infiltration and exhaustion in colorectal cancer predicts cancer immunotherapy response

2020 ◽  
Author(s):  
Sun Tian ◽  
Fulong Wang ◽  
Rongxin Zhang ◽  
Gong Chen
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Infiltration ◽  
Global Pattern ◽  
Cell Exhaustion ◽  
T Cell Infiltration

Abstract MSI/MSS status does not fully explain cancer immunotherapy response in colorectal cancer. We used gene expression data of 454 samples (MSI=131, MSI-L=23, MSS=284, Unknown=16) and developed a method TMEPRE that models colorectal cancer specific signature of CD8+ T cell infiltration and CD8+ T cell exhaustion states. TMEPRE showed predictive power in three datasets of anti-PD1 treated patients(p=0.056, 0.115, 0.003). CD8+ T cell exhaustion component of TMEPRE model correlates with anti-PD1 responding progenitor exhausted CD8+ T cells in both tumor and viral infection(p=0.048, 0.001). Global pattern of TMEPRE on 454 colorectal cancer samples indicated that 10.6% of MSS patients and 67.2% of MSI patients show biological characters that can benefit from anti-PD1 treatment. Within MSI nonresponders, approximately 50% showed no sufficient amount of tumor infiltrating CD8+ T cells and 50% showed terminal exhaustion of CD8+ T cells. These terminally exhausted CD8+ T cells coexisted with signature of myeloid-derived suppressor cells in colorectal cancer.

Regulatory T Cells Prevent Effector T Cell Infiltration Into GvHD Target Tissue by Affecting Chemokine Signaling.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1341-1341 ◽  
Author(s):  
Brie Turner ◽  
Shaheda Ahmed ◽  
Sarah Pagan ◽  
Jean Norden ◽  
Matthew Collin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Chemokine Receptors ◽  
Effector T Cells ◽  
Cell Infiltration ◽  
Cell Surface Expression ◽  
Effector T Cell ◽  
T Cell Infiltration

Abstract Abstract 1341 Poster Board I-363 Introduction Graft versus host disease (GVHD) following haematopoietic stem cell transplantation is often first observed in the skin; a primary target organ of GVHD. GVH related tissue damage in the skin is mainly driven by infiltrating alloreactive cytotoxic effector T cells, facilitated by a cascade of cytokines and chemokines. Our recently published observations showed that addition of regulatory T cells (Treg) suppressed skin GVH tissue damage mediated by alloreactive CD8+ T cells in an in vitro human GVHD skin explant model [1]. The current study investigated the role of Treg in modulating effector T cell infiltration into skin, it's consequence on the severity of skin GVH histopathology and the possible changes of effector T cell production and expression of chemokines and chemokine receptors. Methods CD8+ T cells, monocyte derived dendritic cells (mDC) and natural Treg (CD4+CD2highFOXP3+) were generated as previously described [1]. In an in vitro human GVHD skin explant model, CD8+ T cells and ex vivo expanded Treg obtained from buffy coats were used as “donor” cells. mDC and skin biopsies obtained from HLA unmatched unrelated normal volunteers acted as “recipient” tissues. “Donor” CD8+ T cells primed with “recipient” mDC in the presence or absence of Treg were co-cultured with “recipient” skin. The severity of histopathological GVH skin damage was scored as grade 0 to grade IV using a clinically validated scoring system. The number of infiltrating CD8+ T cells in skin was evaluated using immunohistochemistry then correlated to the severity of skin GVH histopathology. The gene expression of selected chemokines and chemokine receptors in alloreactive CD8+ effector T cells was analysed using quantitative RT-PCR. The effector T cell expression of chemokine receptors was assessed using flow cytometry. The secretion of selected chemokines into the culture supernatants was quantified using BD cytometric bead array kit. Results The percentage of infiltrating effector T cells in skin was significantly associated with the severity of skin GVH histopathology (2.6±0.8, 12.6±3.1 and 27.2±2.7 for skin sections with GVH histopathology grade I, II and III-IV; p=0.017 and 0.021 respectively). The percentage of skin infiltrating CD8+ T cells was significantly reduced by the presence of Treg (24.8±3.7 vs 11.58±1.8, p=0.011, n=13) which correlated with Treg mediated suppression of skin GVH histopathology (p<0.0001, n=13). The presence of Treg also down-regulated effector T cell expression of chemokine/chemokine receptor genes (CCL3, CCL5, CCR4, CCR5, CXCL10 and CXCL11) that are involved in the recruitment of effector T cells to GVH target tissues. Further analysis indicated a trend toward reduced effector T cell surface expression of CCR4 and CCR5 (31.9±4.3 vs 12.5±2.7; 13.7±1.8 vs 8.8±4.1 respectively, n=3) in the presence of Treg. There was also a reduction in CX3CR1 and cutaneous lymphocyte associated antigen (CLA) (11.1±1.9 vs 2.2±0.6; 34.6%±7.0 vs 11.6±2.2 respectively, n=3). The effector T cell surface expression of CXCR3, CCR2 and CCR10 was very low regardless of the presence or absence of Treg. Release of CCL3, CCL5, CXCL9 and CXCL10 into the culture supernatant was strongly suppressed by the presence of Treg (813±122 vs 77±30; 816±248 vs 405±148; 5517±967 vs 974±540 and 858±209 vs 195±57, p=0.001, 0.065, 0.002 and 0.015 respectively, n=8). However, CXCL11 and CX3CL1 levels were below detectable limits regardless of the presence or absence of Treg. Conclusions Ex vivo expanded natural Treg can inhibit CD8+ effector T cell infiltration into skin which correlated with Treg suppression of cytotoxic T cell mediated skin GVH histopathology in an in vitro human GVHD model. This effect may be attributed to a decrease in chemokine and chemokine receptor interactions mediated by Treg. These observations indicate a potential mechanism for Treg mediated GVHD suppression. [1] X N Wang et al., Transplantation 2009 Disclosures No relevant conflicts of interest to declare.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

scholarly journals Spatiotemporal single-cell profiling of gastrointestinal GVHD reveals invasive and resident memory T cell states

2020 ◽  
Author(s):  
Victor Tkachev ◽  
James Kaminski ◽  
E. Lake Potter ◽  
Scott N. Furlan ◽  
Alison Yu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cd8 T Cell ◽  
Transcriptomic Analysis ◽  
Cell Infiltration ◽  
Cell Transplant ◽  
Gi Tract ◽  
Tissue Invasion ◽  
T Cell Infiltration

ABSTRACTOne of the central challenges in the field of allo-immunity is deciphering the mechanisms driving T cells to infiltrate and subsequently occupy target organs to cause disease. The act of CD8-dominated T cell infiltration is critical to acute graft-versus-host disease (aGVHD), wherein donor T cells become activated, tissue-infiltrating and highly cytotoxic, causing wide-spread tissue damage after allogeneic hematopoietic stem cell transplant (allo-HCT). However, in human and non-human primate studies, deconvolving the transcriptional programs of newly recruited relative to resident memory T cells in the gastrointestinal (GI) tract has remained a challenge. In this study, we combined the novel technique of Serial Intravascular Staining (SIVS) with single-cell RNA-Seq (scRNA-seq) to enable detailed dissection of the tightly connected processes by which T cells first infiltrate tissues and then establish a pathogenic tissue residency program after allo-HCT in non-human primates. Our results have enabled the creation of a spatiotemporal map of the transcriptional drivers of CD8 T cell infiltration into the primary aGVHD target-organ, the GI tract. We identify the large and small intestines as the only two sites demonstrating allo-specific, rather than lymphdepletion-driven T cell infiltration. The donor CD8 T cells that infiltrate the GI tract demonstrate a highly activated, cytotoxic phenotype while simultaneously rapidly developing canonical tissue-resident memory (TRM) protein expression and transcriptional signatures, driven by IL-15/IL-21 signaling. Moreover, by combining SIVS and transcriptomic analysis, we have been able to work backwards from this pathogenic TRM programing, and, for the first time, identify a cluster of genes directly associated with tissue invasiveness, prominently including specific chemokines and adhesion molecules and their receptors, as well as a central cytoskeletal transcriptional node. The clinical relevance of this new tissue invasion signature was validated by its ability to discriminate the CD8 T cell transcriptome of patients with GI aGVHD. These results provide new insights into the mechanisms controlling tissue infiltration and pathogenic CD8 TRM transcriptional programing, uncovering critical transitions in allo-immune tissue invasion and destruction.One sentence summaryFlow cytometric and transcriptomic analysis reveals coordinated tissue-infiltration and tissue-residency programs driving gastrointestinal aGVHD.

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