Cytotoxic CX3CR1+ Vδ1 T cells clonally expand in an interplay of CMV, microbiota, and HIV-1 persistence in people on antiretroviral therapy
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ABSTRACT:
PROVIDER: PRJNA1295425 | ENA |
REPOSITORIES: ENA
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Project description:We performed a comprehensive characterization of Vδ1 T cells in blood of people with HIV-1 on antiretroviral therapy and HIV-seronegative controls, in a substudy of the ANRS EP61 GALT study (NCT02906137). We deciphered the single-cell transcriptome of Vδ1 cells. Vδ1 T cells were mainly terminally differentiated effectors that expanded in the blood with some trafficking with the gut of people with HIV-1. Most expressed CX3CR1 and displayed a highly cytotoxic profile, but low cytokine production, supported by a transcriptomic shift towards enhanced effector lymphocytes. The increase in Vδ1 T cells observed in people with HIV-1 has multiple triggers, particularly CMV and microbiota, and may in turn contribute to the control of the HIV-1 reservoir.
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Project description:Impairment and exhaustion of effector functions limiting a proper immune response have been reported for conventional T cells in chronic infection and cancer. However, the functional relevance of γδ T cells influenced by the tumor microenvironment in human colorectal cancer (CRC) is still unclear. Here, we identify and characterize a distinct population of Vδ1+ T cells in human microsatellite stable CRC. Using integrated gene expression analysis and ⍺β/γδ-T cell receptor sequencing, we demonstrate activated adaptive immune responses in Vδ1+ T cells in CRC, which are accompanied by perturbances of innate immunity. However, enhanced upregulation of exhaustion genes, altered effector and cell stress molecules in Vδ1+ T cells pinpoint to impaired γδ T cells in CRC compared to distant healthy colon. Cellular interaction analysis highlights a role of cancer-associated fibroblasts in the dysregulation of Vδ1+ T cells in CRC. Immunophenotyping identified a distinct population of Vδ1+ T cells which dominates the γδ T cell subsets and displays a functionally impaired phenotype with a potential to be restored in vitro. These results define pathways operative in γδ T cells in CRC and provide a roadmap for harnessing γδ T cells for specific immunotherapeutic strategies.
2024-07-11 | GSE236384 | GEO
Project description:The aging brain shows changes in microglial function, morphology, and phenotype, indicating chronic microglial activation. CX3CR1 is crucial for microglial chemotaxis, phagocytosis, and activation. However, its exact role in the aging brain is not well understood. In this study, we examined the expression of CX3CR1 in the brains of middle-aged mice (10 months old) and explored its functional implications by conducting proteomic profiling in CX3CR1-deficient mouse cerebrum. Proteomic analysis revealed an enrichment of differentially expressed proteins (DE-proteins) in the cerebrum of middle-aged mice in GO pathways such as “synapse”, “translation”, and “ribosome”. CX3CR1 deficiency affected protein levels in GO pathways such as “glutamatergic synapse” and “RNA splicing.” We also detected the proteomics in age-matched 5xFAD mice for comparison, since this mouse strain featured aberrant microglial activation and CX3CR1 upregulation in the hippocampus and frontal cortex. Our findings demonstrated that CX3CR1 was upregulated to maintain synaptic homeostasis probably through regulating microglial activation and phagocytosis in the brains of middle-aged mice. CX3CR1 may represent a promising therapeutic target for alleviating the effects of aging and preventing neurodegeneration.
2025-07-05 | PXD058961 | Pride
Project description:Single-cell transcriptomic technologies offer unprecedented resolution to uncover cellular heterogeneity and lineage trajectories. By integrating newly generated and public single-cell RNA sequencing (scRNA-seq) datasets, we analyzed ~119k γδ T cells from 225 individuals spanning the human lifespan (0–90 years). We constructed a comprehensive γδ T cell atlas of 10 transcriptionally distinct clusters with marked age-associated shifts, including a progressive decline of CCR9⁺SOX4⁺ naïve Vδ1 subset and a striking transition from GZMK+ to GZMB+ cells at both RNA and protein levels. Moreover, aged γδ T cells were also characterized by diminished mitochondrial and developmental programs alongside enrichment of effector modules. The pronounced baseline differences between neonates and adults, particularly the low cytotoxic signatures in neonates, prompted us to focus on neonatal–adult comparisons in the context of acute cytomegalovirus (CMV) infection. Our analysis reveals that both neonates and adults mounted robust Vδ1 T cell responses but via distinct strategies. Neonatal Vδ1 T cells underwent de novo effector differentiation alongside balanced Type1- and Type2-associated transcriptional profiles (e.g., IL4R and ICOS). In contrast, adult Vδ1 T cells, already pre-armed for cytotoxic signatures at steady state, responded primarily through proliferative expansion and Type1-skewed antiviral programs (e.g., IFNG and IFITM3). This suggests that neonatal γδ T cells, by tempering inflammatory polarization while mounting an effective response, may mitigate potential immunopathology and safeguard the developing immune system. Taken together, our study delineates the developmental and aging trajectories of human γδ T cells, uncovers age-specific antiviral strategies, and provides a resource for understanding γδ T cell biology in health and infection.
2026-08-26 | GSE306377 | GEO
Project description:Single-cell transcriptomic technologies offer unprecedented resolution to uncover cellular heterogeneity and lineage trajectories. By integrating newly generated and public single-cell RNA sequencing (scRNA-seq) datasets, we analyzed ~119k γδ T cells from 225 individuals spanning the human lifespan (0–90 years). We constructed a comprehensive γδ T cell atlas of 10 transcriptionally distinct clusters with marked age-associated shifts, including a progressive decline of CCR9⁺SOX4⁺ naïve Vδ1 subset and a striking transition from GZMK+ to GZMB+ cells at both RNA and protein levels. Moreover, aged γδ T cells were also characterized by diminished mitochondrial and developmental programs alongside enrichment of effector modules. The pronounced baseline differences between neonates and adults, particularly the low cytotoxic signatures in neonates, prompted us to focus on neonatal–adult comparisons in the context of acute cytomegalovirus (CMV) infection. Our analysis reveals that both neonates and adults mounted robust Vδ1 T cell responses but via distinct strategies. Neonatal Vδ1 T cells underwent de novo effector differentiation alongside balanced Type1- and Type2-associated transcriptional profiles (e.g., IL4R and ICOS). In contrast, adult Vδ1 T cells, already pre-armed for cytotoxic signatures at steady state, responded primarily through proliferative expansion and Type1-skewed antiviral programs (e.g., IFNG and IFITM3). This suggests that neonatal γδ T cells, by tempering inflammatory polarization while mounting an effective response, may mitigate potential immunopathology and safeguard the developing immune system. Taken together, our study delineates the developmental and aging trajectories of human γδ T cells, uncovers age-specific antiviral strategies, and provides a resource for understanding γδ T cell biology in health and infection.
2026-08-26 | GSE306534 | GEO
Project description:We focus on characterizing Vδ1 T cell development through determination of their effector profile, characterization of their paired TCR repertoire, and understanding of antigen reactivity towards CD1 molecules through single cell RNA analyses.
2026-02-13 | GSE269123 | GEO
Project description:Checkpoint inhibition (CPI), particularly that targeting the inhibitory co-receptor, programmed cell death protein (PD-1), has transformed cancer care. Although CPI can de repress cancer antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition. In such settings γδ T cells have been implicated, but the immunological significance of PD-1 expression by tissue associated human Vδ1+ cells remains uncharacterised. Here we demonstrate that a transcriptional signature of intratumoral Vδ1+ cells predicts response to anti-PD-1 in patients with melanomas of relatively low neoantigen load. Moreover, by employing a protocol yielding substantial numbers of human skin γδ cells, we show that PD-1+ Vδ1+ cells display a transcriptomic programme of tissue-residence, survival/self-renewal, and functional competence distinct from the canonical exhaustion programme of co-located PD- 1+ CD8+ αβ T cells. Indeed, skin PD-1+ Vδ1+ cells retained effector responses to T cell receptor signalling that were inhibitable by PD-1 engagement and partially derepressed by CPI. The biological and therapeutic implications are both discussed.
2023-09-25 | GSE232529 | GEO
Project description:We conducted immune- and RNA-sequencing of HLA-A24-restricted CMVpp65-specific CTLs to better understand the immune reconstitution of CMV-CTLs after allo-HCT. To the best of our knowledge, this is the first report on the features of TCRβ-CDR3, diversity, and GEP of HLA-A24 CMV-CTLs according to the CMV-reactivation pattern among recipients after allo-HCT. In addition, we further sought to demonstrate homogeneity or heterogeneity according to individual CTL clones using single-cell RNA-sequencing technology.
2021-01-01 | GSE156841 | GEO
Project description:Interventions: Patients with the detection of either cytomegalic cells or IHC-CMV cells were diagnosed with CMV colitis.,Patients older than 18 years with clinical suspicion of CMV colitis but negative biopsy for CMV.,Asymptomatic patients underwent colonoscopy for screening.;Diagnostic,Diagnostic,Diagnostic;CMV colitis,Non-CMV colitis ,Healthy volunteers
Primary outcome(s): Diagnostic performance After colonoscopy Sensitivity, Specificity
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