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Results for “Perforin”

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4 recordsLinked to original sources

PubMed2013

MicroRNA-directed program of cytotoxic CD8+ T-cell differentiation.

Acquisition of effector properties is a key step in the generation of cytotoxic T lymphocytes (CTLs). Here we show that inflammatory signals regulate Dicer expression in CTLs, and that deletion or depletion of Dicer in mouse or human activated CD8(+) T cells causes up-regulation of perforin, granzymes, and effector cytokines. Genome-wide analysis of microRNA (miR, miRNA) changes induced by exposure of differentiating CTLs to IL-2 and inflammatory signals identifies miR-139 and miR-150 as components of an miRNA network that controls perforin, eomesodermin, and IL-2Rα expression in differentiating CTLs and whose activity is modulated by IL-2, inflammation, and antigenic stimulation. Overall, our data show that strong IL-2R and inflammatory signals act through Dicer and miRNAs to control the cytolytic program and other aspects of effector CTL differentiation.

Adoptive Transfer↗

PubMed2025

An Immunosenescent CD8+ T Cell Subset in Patients with Axial Spondyloarthritis and Psoriatic Arthritis Links Spontaneous Motility to Telomere Shortening and Dysfunction.

OBJECTIVE: A pathogenetic role of CD8+ T lymphocytes in radiographic axial spondyloarthritis (r-axSpA) and other spondyloarthritis (SpA) is sustained by genome-wide association studies and by the expansion of public T cell clonotypes in the target tissues. This study investigates the migration of CD8+ T cells along with their phenotype and functions in patients with r-axSpA and psoriatic arthritis (PsA). METHODS: Peripheral blood CD8+ and CD4+ T cells were isolated from patients with r-axSpA (n = 128), PsA (n = 60), and rheumatoid arthritis (RA) (n = 74) and healthy donors (HDs) (n = 79). Transwell migration assay was performed in the presence of different chemokines. CD8+ T cell immunoprofiling and effector functions were assessed by multiparametric flow cytometry. Transcriptome signature was evaluated by RNA sequencing analysis, whereas telomere length and dysfunction were measured by reverse transcriptase-polymerase chain reaction and immunofluorescence-fluorescence in situ hybridization, respectively. RESULTS: A significantly higher number of CD8+ T cells migrating in the absence of chemokine stimuli was found in patients with SpA compared with HDs and patients with RA. This subset, producing cytotoxic (granzyme B, perforin, granulysin) and proinflammatory molecules (tumor necrosis factor), was significantly enriched in terminally differentiated (CCR7-CD45RA+) and senescent (CD28-CD57+) cells having a gene expression profile characterized by cytolytic signature and natural killer markers. Remarkably, these spontaneously migrating CD8+ T cells showed DNA damage response activation, telomere shortening, and dysfunction. CONCLUSION: These data describe a terminally differentiated CD8+ T cell subset with a senescent and cytotoxic/proinflammatory profile and an intrinsic invasive potential enriched in patients with SpA that represents a possible player in disease pathogenesis.

Humans↗

PubMed2026

Intratumoral PD-1+LAG-3+CD8+ T cells are associated with improved prognosis in gastric cancer.

PURPOSE: PD-1 and LAG-3 are frequently used as markers of T cell exhaustion, yet the prognostic relevance and phenotypic characteristics of PD-1+LAG-3+CD8+ T cells in gastric cancer (GC) remain poorly defined. This study aimed to investigate their association with clinical outcomes and characterize their immune characteristics across independent GC cohorts. METHODS: Four independent GC cohorts were analyzed: the Zhongshan Hospital cohort (ZSGC, n = 298), The Cancer Genome Atlas cohort (TCGA, n = 371), an Immune Checkpoint Blockade cohort (ICB, n = 45), and the Yonsei cohort (n = 433). Intratumoral PD-1+LAG-3+CD8+ T cell infiltration was quantified by immunofluorescence staining and transcriptomic gene signature scoring. Survival analysis was performed using Kaplan-Meier estimation and multivariate Cox regression. Functional characterization was performed by flow cytometry on resected GC tissue. The immune microenvironment composition was evaluated using computational analyses. RESULTS: PD-1+LAG-3+CD8+ T cells were enriched within tumors compared to adjacent normal mucosa, and their infiltration correlated with advanced tumor stage, poor differentiation, microsatellite instability, and Epstein-Barr virus (EBV)-positive molecular subtypes. High intratumoral infiltration was significantly associated with improved overall survival in both the ZSGC and TCGA cohorts, whereas single-positive PD-1+CD8+ or LAG-3+CD8+ T cells showed no such association. In the ICB cohort, higher infiltration was associated with a higher response rate to pembrolizumab. Intratumoral PD-1+LAG-3+CD8+ T cells exhibit an activated phenotype characterized by increased expression of CD137, IFN-γ, perforin, and CXCL13, along with elevated TCF7 and lower PD-1 levels, suggesting a tumor-reactive, pre-exhausted state. High infiltration was further associated with an immune-active tumor microenvironment. CONCLUSIONS: High intratumoral infiltration of PD-1+LAG-3+CD8+ T cells is associated with favorable prognosis and an immune-active microenvironment in GC. These cells display phenotypic features consistent with a pre-exhausted state and may serve as independent prognostic biomarkers and candidate predictive biomarkers for immunotherapy stratification.

Humans↗

PubMed2015

Dengue virus infection elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated with protective immunity.

Dengue virus (DENV) is a rapidly spreading pathogen with unusual pathogenesis, and correlates of protection from severe dengue disease and vaccine efficacy have not yet been established. Although DENV-specific CD8(+) T-cell responses have been extensively studied, the breadth and specificity of CD4(+) T-cell responses remains to be defined. Here we define HLA-restricted CD4(+) T-cell epitopes resulting from natural infection with dengue virus in a hyperepidemic setting. Ex vivo flow-cytometric analysis of DENV-specific CD4(+) T cells revealed that the virus-specific cells were highly polarized, with a strong bias toward a CX3CR1(+) Eomesodermin(+) perforin(+) granzyme B(+) CD45RA(+) CD4 CTL phenotype. Importantly, these cells correlated with a protective HLA DR allele, and we demonstrate that these cells have direct ex vivo DENV-specific cytolytic activity. We speculate that cytotoxic dengue-specific CD4(+) T cells may play a role in the control of dengue infection in vivo, and this immune correlate may be a key target for dengue virus vaccine development.

Adult↗