Tumor-reactive heterotypic CD8 T cell clusters from clinical samples
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PROVIDER: PRJNA1196361 | ENA |
REPOSITORIES: ENA
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Project description:Emerging evidence suggests a correlation between CD8+ T cell-tumor cell proximity and immunotherapy response1–3. However, it is unknown whether these cells can be captured as functional clusters from clinical samples. In defined human co-cultures, tumor antigen-recognizing T cells outcompeted unmatched T cells in forming clusters with tumor cells, prompting us to investigate whether this feature could be used to isolate tumor-reactive T cells directly from cancer specimens. By conventional and imaging flow cytometry, we show here that from 21/21 human melanoma metastases, we were able to isolate heterotypic clusters, comprising CD8+ T cells interacting with one or more tumor cells and/or antigen-presenting cells (APCs). Single cell RNA-sequencing revealed that CD8+ T cells from clusters were enriched for tumor-reactive and exhausted gene signatures. Integration with T cell receptor (TCR)-sequencing showed increased clonality of clustered T cells, indicative of expansion. In-depth analyses revealed that these T cells had conjugated with tumor cells and various APCs, each exhibiting specific enriched cell states, which were linked to distinct patterns of cell-cell communication. CD8+ T cells expanded from clusters ex vivo exerted on average 9-fold increased killing activity towards autologous melanomas, accompanied by enhanced cytokine production. Also upon adoptive cell transfer (ACT) into mice, T cells from clusters showed superior patient-derived xenograft (PDX) killing associated with more T cell infiltration and activation. Together, these results demonstrate that tumor-reactive CD8+ T cells are enriched in functional clusters with tumor cells and/or APCs, and that they can be isolated and expanded from clinical samples. Typically excluded during single-cell sorting by flow cytometry, these distinct heterotypic CD8+ T cell clusters serve as a valuable source amenable to deciphering functional tumor-immune cell interactions, while they may also be therapeutically explored.
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Project description:CD8+ T cells play a critical role in immune tolerance maintainnance after immune activation. It is known to function through targeting activated CD4+ T cells, in both Qa-1- and MHC-Ia-restricted9 manner. However, the exact nature of this targeting process, i.e., the specific peptides and the corresponding reactive CD8 TCRs, remains unknown. In this study, we identified the self-peptides on activated CD4+ T cells that could mediate the CD8+ T cells immunosuppressive activity. By cloning the corresponding CD8 TCRs and the generation of TCR transgenic mice , we were able to validate the immunosuppressive function of CD8+ T cells carrying the self-reactive TCRs both in vitro and in vivo. The therapeutic potential of peptide vaccination and CD8+ T cell transfer were confirmed in a mouse EAE model. This study suggest that self-tolerance can be maintained by self-reactive CD8+ T cells recognizing self-antigenic peptides through specific TCRs, thus redefine the nature of CD8+ regulatory T cells as self-reactive CD8+ T cells.
2025-08-30 | GSE276227 | GEO
Project description:CD8+ T cells play a critical role in immune tolerance maintainnance after immune activation. It is known to function through targeting activated CD4+ T cells, in both Qa-1- and MHC-Ia-restricted9 manner. However, the exact nature of this targeting process, i.e., the specific peptides and the corresponding reactive CD8 TCRs, remains unknown. In this study, we identified the self-peptides on activated CD4+ T cells that could mediate the CD8+ T cells immunosuppressive activity. By cloning the corresponding CD8 TCRs and the generation of TCR transgenic mice , we were able to validate the immunosuppressive function of CD8+ T cells carrying the self-reactive TCRs both in vitro and in vivo. The therapeutic potential of peptide vaccination and CD8+ T cell transfer were confirmed in a mouse EAE model. This study suggest that self-tolerance can be maintained by self-reactive CD8+ T cells recognizing self-antigenic peptides through specific TCRs, thus redefine the nature of CD8+ regulatory T cells as self-reactive CD8+ T cells.
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2025-06-25 | GSE300584 | GEO
Project description:Poor immune reconstitution following haematopoietic stem cell transplantation (HSCT) can cause unwanted and harmful sequelae in recipients with chronic cytomegalovirus (CMV) infection. To understand the molecular mechanisms underlying poor reconstitution, we profiled the transcriptome-chromatin accessibility landscape of CMV-specific CD8+ memory lymphocytes from HCST recipients with different reconstitution efficiencies. Although the transcriptional and epigenomic signatures in non-reactive lymphocytes were not naïve or classic ‘exhaustion’ profiles, some gene expression was common to lymphocytes from other non-resolving infections. Reactive lymphocytes expressed higher levels of interferon/defence response and cell cycle genes in an interconnected network involving PI3KCG, STAT5B, NFAT, RBPJ, and NR3C1, increasing chromatin accessibility at the enhancer regions of immune and T cell receptor signalling pathway genes. We propose that increased HDAC6 expression in non-reactive lymphocytes decreases accessibility at particular enhancers including PI3KCG. Non-reactive cells also expressed higher levels of EGR and KLF factors that, along with lower expression of JARID2, maintained higher accessibility at promoter and CpG-rich regions of genes associated with apoptosis. Together, transcription factors and chromatin modulators create a different chromatin accessibility landscape in reactive and non-reactive cells that not only affects immediate gene expression but differentially primes the cells for responses to additional signals.
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Project description:Self-tolerance maintained by self-reactive CD8+ T cells
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