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Functionally heterogeneous intratumoral CD4+CD8+ double positive T cells can give rise to single positive T cells [bulkRNA-seq]

ABSTRACT: Conventional single positive (SP) CD4+ and CD8+ T cells recognize tumor antigens and help mediate clinical responses with cancer immunotherapy. Double positive CD4+CD8+ (DP) T cells have also been described in human cancers, but their role in the tumor microenvironment (TME) remains unclear. By generating a multi-omic single cell atlas of DP and SP T cells, we find that DP T cells possess phenotypic heterogeneity similar to SP T cells that includes multiple clonally expanded populations of cytotoxic DP T cells in human renal cell carcinoma (RCC). These intratumoral DP T cells can mediate by both MHC class I- and class II-dependent killing of autologous tumor cells. In addition, transcriptional profiling of DP TCR-bearing T cells revealed a gene signature enriched for clinical responders to PD-1 blockade in advanced RCC. We confirm prior observations of SP T cells transitioning into DP T cells and more notably, demonstrate that intratumoral T cells are capable of bidirectional differentiation in which DP T cells serve as precursors to SP T cells in vivo. In the latter scenario, intratumoral DP T cells are shown to express Rag2, suggesting that the tumor may act as an extrathymic site of T cell development. These findings reveal the multiple roles that DP T cells can possess in anti-tumor immunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE314071 | GEO | 2026/01/01

REPOSITORIES: GEO

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Functionally heterogeneous intratumoral CD4+CD8+ double positive T cells can give rise to single positive T cells [scRNA-seq + scTCR-seq]

Project description:Conventional single positive (SP) CD4+ and CD8+ T cells recognize tumor antigens and help mediate clinical responses with cancer immunotherapy. Double positive CD4+CD8+ (DP) T cells have also been described in human cancers, but their role in the tumor microenvironment (TME) remains unclear. By generating a multi-omic single cell atlas of DP and SP T cells, we find that DP T cells possess phenotypic heterogeneity similar to SP T cells that includes multiple clonally expanded populations of cytotoxic DP T cells in human renal cell carcinoma (RCC). These intratumoral DP T cells can mediate by both MHC class I- and class II-dependent killing of autologous tumor cells. In addition, transcriptional profiling of DP TCR-bearing T cells revealed a gene signature enriched for clinical responders to PD-1 blockade in advanced RCC. We confirm prior observations of SP T cells transitioning into DP T cells and more notably, demonstrate that intratumoral T cells are capable of bidirectional differentiation in which DP T cells serve as precursors to SP T cells in vivo. In the latter scenario, intratumoral DP T cells are shown to express Rag2, suggesting that the tumor may act as an extrathymic site of T cell development. These findings reveal the multiple roles that DP T cells can possess in anti-tumor immunity.

2026-01-01 | GSE314072 | GEO

Analysis of Differentially Expressed Genes in sorted CD69+ double positive (DP) thymocytes from wild type (WT) and NSRP1CD4Cre (KO) mice

Project description:NSrp70 deficiency (NSRP1f/fCD4Cre) profoundly perturbed the late development of DP thymocytes, leading to a significant reduction of single positive (SP) cells in the thymus and peripheral lymphoid tissues. To gain further insight into how NSrp70 controls thymocyte development from CD69+ DP stage, we performed RNA-seq analysis after sorting CD69+ DP thymocytes from WT and Nsrp1 cKO mice.

2020-06-27 | GSE153389 | GEO

A population of CD4+CD8+ double-positive T cells associated with risk of plasma leakage in dengue viral infection

Project description:According to the WHO 2009 classification, dengue with warning signs (D+W) is at the risk of developing severe form of dengue disease. One of the most important warning signs is plasma leakage, which is a serious complication associated with higher morbidity and mortality. We report that the frequency of CD4+CD8+ double-positive (DP) T cells is significantly increased in patients at risk of developing plasma leakage. Transcriptomic analysis demonstrated that CD4+CD8+ DP cells were distinct from CD4+ Single Positive (SP) T cells, but co-clustered with CD8+ SP cells indicating a largely similar transcriptional profile. 20 significant differentially expressed (DE) genes were identified between CD4+CD8+ DP and CD8+ SP cells. These genes encode OX40 and CCR4 (TNFRSF4 and CCR4), as well as other molecules associated with cell signaling on the cell surface (NT5E, MXRA8, PTPRK). While 5 significant DE genes were identified, the profile of gene expression in CD4+CD8+ DP cells was mostly similar between patients with and without warning signs of plasma leakage, implying a role of CD4+CD8+ DP cells in plasma leakage through a quantitative increase rather than functional alteration. The differentially expressed genes identified could have diagnostic utility, perhaps as PCR-based diagnostic markers.

2021-06-16 | GSE178240 | GEO

Analysis of Differentially Expressed Genes in sorted CD4+ CD8+ doubl positive (DP) thymocytes from wild type (WT) and NSRP1CD4Cre (KO) mice

Project description:NSrp70 deficiency (NSRP1f/fCD4Cre) profoundly perturbed the late development of DP thymocytes, leading to a significant reduction of single positive (SP) cells in the thymus and peripheral lymphoid tissues. To gain further insight how NSrp70 controls thymocyte development from DP stage, we performed RNA-seq analysis after sorting DP thymocytes from WT and Nsrp1 cKO mice.

2021-06-15 | GSE168379 | GEO

The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during positive selection in the thymus

Project description:Here we show that the pioneer transcription factors Foxa1 and Foxa2 are required to regulate RNA splicing during positive selection at the transition from CD4+CD8+ double positive (DP) to single positive (SP thymocyte). Conditional deletion of both Foxa1 and Foxa2 from DP thymocytes led to a partial arrest at the transition from DP to SP, with a reduction in the number of cells undergoing positive selection, and reduced the number and maturation of both CD4SP and CD8SP populations, with a reduction in peripheral naïve CD4+ T-cells. Foxa1 and Foxa2 were required for physiological levels of expression of several genes which encoding splicing factors (Mbnl1, Sf3b1, Hnrnpa1) in cells undergoing positive selection. Within the positively selecting CD69+DP cells, alternative RNA splicing was dysregulated leading to more than 859 significantly differentially expressed exons compared to control, with many genes important for T cell development and for RNA splicing showing differentially used exons.

2021-07-13 | GSE169602 | GEO

Analysis of blood myelomonocytic cells from RCC patients

Project description:Myelomonocytic cells (i.e., monocytes or macrophages) play a key role in tumor progression as revealed by numerous mice tumor model studies. However, their contribution in human tumor progression is not well-studied. Using Renal Cell Carcinoma (RCC) as a model for human cancer, we performed a transcriptomal profiling of blood monocytes from RCC patients to investigate the contribution of these cells in cancer progression. As compared to monocytes from healthy donors (Mo), transcriptome analysis of monocytes from RCC patients (RCC-Mo) showed a distinct gene expression signature consisting of cytokines, chemokines and various inflammation-related genes. Validation of these genes by qPCR as well as other functional assays indicated RCC-Mo possess an inflammatory and tumor promoting phenotype. Blood monocytes from RCC patients (with early or metastatic disease) or healthy donors (controls) were isolated, and then differential gene expression was detected with Limma.

2014-10-30 | E-GEOD-38424 | biostudies-arrayexpress

Analysis of blood myelomonocytic cells from RCC patients

2014-10-30 | GSE38424 | GEO

Gene expression of CD4+CD8+ Tfh cells and CD4+CD8- Tfh in tonsil.

Project description:To understand physiological characteristics of CD4+CD8+ Double-positive (DP)-Tfh cells, we continued to conduct comparative transcriptome analysis of tonsillar Tfh cell populations, including DP-Tfh cells and CD4+CD8- single-positive (SP)-Tfh cells as a control. Results showed that DP-Tfh cells preferentially expressed transcripts related to CTLs, such as CD8 (CD8A and CD8B), Eomes, and granzymes, suggesting a possible cytotoxic attribute of DP-Tfh cells. Th1-cell related signature genes were also presented in DP-Tfh cells and cytokines like interferon (IFN)-gamma and interleukin (IL)-10 were found to be highly presented in DP-Tfh cells rather than SP-Tfh cells. Of note, the expression profile of authentic Tfh-cell (i.e. SP-Tfh cell) related genes like IL-4, IL-21, Bcl6, and Pou2af1 seemed to be shared with DP-Tfh cells.

2022-08-10 | GSE202616 | GEO

Chromatin organizer SATB1 controls the cell identity of CD4+ CD8+ double-positive thymocytes by compacting super-enhancers

Project description:CD4+ and CD8+ double-positive (DP) thymocytes are at a critical stage during the T cell development in thymus. DP cells rearrange the T cell receptor gene Tcra to generate T cell receptors with TCR. Then DP cells differentiate into CD4 or CD8 single-positive (SP) thymocytes, Regulatory T cells, or invariant nature kill T cells (iNKT) according to the TCR signal. Chromatin organizer SATB1 is highly expressed in DP cells and plays an essential role in regulating Tcra rearrangement and differentiation of DP cells. Here we explored the mechanism of SATB1 orchestrating gene expression in DP cells. Single-cell RNA sequencing assay of SATB1-deficient thymocytes showed that the cell identity of DP thymocytes was changed, and the genes specifically highly expressed in DP cells were down-regulated. ChIP-seq and ATAC-seq data showed the similar tendency. The super-enhancers regulate the expressions of the DP-specific genes, and the SATB1 deficiency reduced the super-enhancer activity. Hi-C data showed that interactions in super-enhancers and between super-enhancers and promoters decreased in SATB1 deficient thymocytes. We further explored the regulation mechanism of two SATB1-regulating genes, ETS2 and Bcl6, in DP cells and found that the knockout of the super-enhancers of these two genes impaired the development of DP cells. Our research reveals that SATB1 globally regulates super-enhancers of DP cells and promotes the establishment of DP cell identity, which helps understand the role of SATB1 in thymocyte development.

2021-09-02 | GSE182995 | GEO

Paxbp1 is indispensable for the survival of CD4 and CD8 double-positive thymocytes

Project description:The lifespan of double-positive (DP) thymocytes is critical for intrathymic development and shaping the peripheral T cell repertoire. However, the molecular mechanisms that control DP thymocyte survival remain poorly understood. Paxbp1 is a conserved nuclear protein that has been reported to play important roles in cell growth and development. Its high expression in T cells suggests a possible role in T cell development. Here, we observed that deletion of Paxbp1 resulted in thymic atrophy in mice lacking Paxbp1 in the early stages of T cell development. Conditional loss of Paxbp1 resulted in fewer CD4+CD8+ DP T cells, CD4 and CD8 single positive (SP) T cells in the thymus, and fewer T cells in the periphery. Meanwhile, Paxbp1 deficiency had limited effects on the CD4-CD8- double negative (DN) or immature single-positive (ISP) cell populations. Instead, we observed a significant increase in the susceptibility of Paxbp1-deficient DP thymocytes to apoptosis. Consistent with this, RNA-Seq analysis revealed a significant enrichment of the apoptotic pathway within differentially expressed genes in Paxbp1-deficient DP cells compared to control DP cells. Together, our results suggest a new function for Paxbp1, which is an important mediator of DP thymocyte survival and critical for proper thymic development.

2023-06-14 | GSE233211 | GEO

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