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Divergent clonal differentiation trajectories of T cell exhaustion (scATAC-seq)

ABSTRACT: T cells activated by chronic antigen exposure in the setting of viral infections or cancer can adopt an exhausted T cell (TEx) state, characterized by reduced effector function and proliferative capacity, and the upregulation of inhibitory receptors. Here, we generate a single-cell multi-omic atlas of T cell exhaustion in chronic viral infection that redefines the phenotypic diversity and molecular regulation of TEx states. Longitudinal analysis of the T cell response identifies an early effector phenotype that is epigenetically primed for TEx differentiation. However, clonal T cell trajectories defined using paired single-cell RNA and T cell receptor (scRNA/TCR-seq) sequencing reveal divergent differentiation trajectories among clones that recognize shared antigens, resulting in TEx- or effector memory-biased clone behaviors. Multi-organ clonal analysis reveals that T cell clone behaviors are sensitive to the tissue environment, and the liver niche preclude the development of effector memory phenotypes and induce exaggerated exhaustion. Finally, we show that divergent clonal trajectories are driven by differences in TCR affinity, and that high-affinity T cell clones preferentially adopt the divergent fate, while low-affinity clones adopt effector memory fates that are deleted in high antigen niches. These findings reveal heterogeneity in clonal T cell responses to chronic antigen and link TCR signal strength and epigenetic programming to TEx cell fates and persistence, which may be manipulated for cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE188669 | GEO | 2022/07/25

REPOSITORIES: GEO

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Divergent clonal differentiation trajectories of T cell exhaustion (scRNA-seq)

Project description:T cells activated by chronic antigen exposure in the setting of viral infections or cancer can adopt an exhausted T cell (Tex) state, characterized by reduced effector function and proliferative capacity, and the upregulation of inhibitory receptors. However, whether all antigen-specific T cell clones follow the same molecular and cellular Tex differentiation trajectory remains unclear. Here, we generate a single-cell multi-omic atlas of T cell exhaustion that redefines the phenotypic diversity and molecular regulation of Tex phenotypes. Longitudinal analysis during chronic viral infection identifies an early effector phenotype that is epigenetically primed for Tex differentiation and two late-stage Tex cell states with either a terminal exhaustion or a killer cell lectin-like receptor (KLR)-expressing cytotoxic gene signature. We define clonal trajectories of antigen-specific T cells using paired single-cell RNA and T cell receptor sequencing and reveal distinct differentiation trajectories resulting in terminal Tex-biased, KLR Tex-biased, or divergent clones that differentiate into both phenotypes. Comparison of Tex phenotypes among shared T cell clones that traffic to multiple organs reveals that clonal differentiation trajectories are maintained across tissues. Finally, we show that differences in clonal differentiation trajectory are driven by TCR signaling avidity, whereby high-avidity T cell clones preferentially adopt a terminal Tex fate, while low-avidity clones adopt an effector-like KLR Tex fate. These findings reveal clonal heterogeneity in the T cell response to chronic antigen and genomic programs that underlie Tex fates and persistence.

2022-07-25 | GSE188666 | GEO

The transcription factor IRF4 is essential for T cell receptor affinity mediated metabolic programming and clonal expansion of T cells [RNA-seq]

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Interconnected lineage trajectories link conventional and NK-like exhausted CD8+ T cells beneficial in T1D [P452_3]

Project description:While distinct NK-like CD57+ and PD-1+ CD8+ exhausted T cell populations (Tex) were both linked to beneficial immunotherapy response in autoimmune Type 1 Diabetes (T1D) patients, relationships between these cell types are poorly understood. We show that PD-1+ and CD57+ Tex populations in this context were epigenetically similar, but CD57+ Tex cells displayed unique increased chromatin accessibility of inhibitory Killer Cell Immunoglobulin-like Receptor (iKIR) and other NK cell genes. PD-1+ and CD57+ Tex also showed reciprocal expression of Inhibitory Receptors (IRs) and iKIRs accompanied by chromatin accessibility of Tcf1 and Tbet transcription factor target sites, respectively. CD57+ Tex showed unappreciated gene expression heterogeneity and shared clonal relationships with PD-1+ Tex, with these cells differentiating along four interconnected lineage trajectories: Tex-PD-1+, Tex-CD57+, Tex-Branching, and Tex-Fluid. Our findings demonstrate new relationships between Tex populations in human autoimmune disease and suggest that modulating common precursor populations may enhance response to autoimmune disease treatment.

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Project description:Type 1 diabetes (T1D) is an autoimmune disorder defined by CD8 T cell-mediated destruction of pancreatic β cells. Our previous work has shown that diabetogenic CD8 T cells in the islets of the non-obese diabetic (NOD) mouse model of T1D are phenotypically heterogenous, but CD8 T cell clonal heterogeneity in this model remains relatively unexplored. Here, we use paired single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq) to characterize autoreactive CD8 T cells from the islets and spleens of NOD mice. Clonal analysis of scTCR-seq data demonstrates that CD8 T cells targeting the immunodominant β cell epitope IGRP206-214 exhibit highly restricted TCR gene usage, with over 70% of IGRP206-214-reactive cells utilizing the same TCR V alpha, J alpha, and V beta genes. Despite this, we observe only 5% overlap of IGRP206-214-reactive CD8 T cell clones between two groups of 10 NOD mice, demonstrating the immense TCR heterogeneity generated by junctional diversity during V(D)J recombination. scRNA-seq identifies two new clusters of autoreactive CD8 T cells in the islets and six clusters of diabetogenic CD8 T cells in the spleen, including multiple memory-like clusters and a population of exhausted cells. Strong clonal overlap between IGRP206-214-reactive CD8 T cells in the islets and spleen suggests that these cells may exit the islets and enter the peripheral circulation. Finally, we identify correlations between TCR J beta gene usage, which is less restricted than that of other TCR genes, and CD8 T cell clonal expansion as well as effector fate. Collectively, our work demonstrates that IGRP206-214-specific CD8 T cells are phenotypically heterogeneous but clonally similar, raising the possibility of selectively targeting either conserved or divergent TCR structures of these cells for therapeutic benefit.

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The pseudokinase Trib1 regulates the transition of exhausted T cells to a KLR+ CD8+ effector state and its deletion improves checkpoint blockade

Project description:CD8+ T cell exhaustion (TEX) impairs the ability of T cells to clear chronic infection or cancer. While TEX are hypofunctional, some TEX retain effector gene signatures, a feature that is associated with expression of KLRs (killer lectin-like receptors). Although KLR+ TEX may improve control of chronic antigen, the signaling molecules regulating this population are poorly understood. Using scRNA-seq, flow cytometry, RNA velocity, and scTCR-seq, we demonstrated that deleting the pseudokinase Trib1 shifted TEX towards CX3CR1+ intermediates (TINT) with robust enrichment of KLR+ TEX (TKLR) via clonal T cell expansion. Adoptive transfer studies demonstrate this shift towards a CD8+ TKLR in Trib1 deficient cells is CD8-intrinsic, while CD4-depletion studies demonstrate that CD4+ T cells are required for optimal viral control in Trib1 conditional knockout mice. Further, Trib1 loss augmented anti-PD-L1 blockade to improve viral clearance. These data identify Trib1 as an important regulator of CD8+ TEX whose targeting enhances the TKLR effector state and improves checkpoint inhibitor therapy.

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