Early transcriptional and epigenetic divergence of CD8+ T cells responding to acute versus chronic infection.
Lauren K Quezada, Wenhao Jin, Yi Chia Liu, Eleanor S Kim, Zhaoren He, Cynthia S Indralingam, Tiffani Tysl, Lara Labarta-Bajo, Ellen J Wehrens, Yeara Jo, Katelynn R Kazane, Christopher Hattori, Elina I Zuniga, Gene W Yeo, John T Chang
PLoS biology · 2023 · Vol. 21 (1) · pp. e3001983
Abstract
During a microbial infection, responding CD8+ T cells give rise to effector cells that provide acute host defense and memory cells that provide sustained protection. An alternative outcome is exhaustion, a state of T cell dysfunction that occurs in the context of chronic infections and cancer. Although it is evident that exhausted CD8+ T (TEX) cells are phenotypically and molecularly distinct from effector and memory CD8+ T cells, the factors regulating the earliest events in the differentiation process of TEX cells remain incompletely understood. Here, we performed single-cell RNA-sequencing and single-cell ATAC-sequencing of CD8+ T cells responding to LCMV-Armstrong (LCMV-Arm) or LCMV-Clone 13 (LCMV-Cl13), which result in acute or chronic infections, respectively. Compared to CD8+ T cells that had undergone their first division in response to LCMV-Arm (Div1ARM) cells, CD8+ T cells that had undergone their first division in response to LCMV-Cl13 (Div1CL13) expressed higher levels of genes encoding transcription factors previously associated with exhaustion, along with higher levels of Ezh2, the catalytic component of the Polycomb Repressive Complex 2 (PRC2) complex, which mediates epigenetic silencing. Modulation of Ezh2 resulted in altered expression of exhaustion-associated molecules by CD8+ T cells responding to LCMV-Cl13, though the specific cellular and infectious contexts, rather than simply the level of Ezh2 expression, likely determine the eventual outcome. Taken together, these findings suggest that the differentiation paths of CD8+ T cells responding to acute versus chronic infections may diverge earlier than previously appreciated.
Linked datasets 3
Gene expression profiles at the single cell level of CD8+ T cells from the spleens of LCMV-Armstrong or LCMV-Clone 13 infected mice
Mus musculus
32 data files
| File | Type | Size |
|---|---|---|
| LQ_10X_D22_Arm_R1.fastq.gz | RNA-Seq | 3.2 GB |
| LQ_10X_D3_Arm_final_R1.fastq.gz | RNA-Seq | 4.8 GB |
| LQ_10X_D3_Cl13_R1.fastq.gz | RNA-Seq | 2.9 GB |
| LQ_10X_D5_Arm_R1.fastq.gz | RNA-Seq | 5.0 GB |
| LQ_10X_D60_Arm_R1.fastq.gz | RNA-Seq | 6.2 GB |
| LQ_10X_D60_Cl13_R1.fastq.gz | RNA-Seq | 5.1 GB |
| LQ_10X_D6_Arm_R1.fastq.gz | RNA-Seq | 1.7 GB |
| LQ_10X_D7_Arm_R1.fastq.gz | RNA-Seq | 2.5 GB |
| LQ_10X_D8_Arm_R1.fastq.gz | RNA-Seq | 2.4 GB |
| LQ_10X_D8_Cl13_R1.fastq.gz | RNA-Seq | 6.5 GB |
| LQ_10X_Div_1_Arm_R1.fastq.gz | RNA-Seq | 4.5 GB |
| LQ_10X_Div_1_Cl13_R1.fastq.gz | RNA-Seq | 4.5 GB |
| LQ_10X_Naive_R1.fastq.gz | RNA-Seq | 5.6 GB |
| LQ_D22_Cl13_Re-do_R1.fastq.gz | RNA-Seq | 2.1 GB |
| LQ_D34_Cl13_Re-do_R1.fastq.gz | RNA-Seq | 1.9 GB |
| LQ_D5_Cl13_Re-Do_R1.fastq.gz | RNA-Seq | 2.6 GB |
| SRR21594696_GSM6586838 | RNA-Seq | 5.0 GB |
| SRR21594697_GSM6586837 | RNA-Seq | 4.8 GB |
| SRR21594698_GSM6586836 | RNA-Seq | 4.5 GB |
| SRR21594699_GSM6586835 | RNA-Seq | 5.6 GB |
| SRR21594700_GSM6586850 | RNA-Seq | 5.1 GB |
| SRR21594701_GSM6586849 | RNA-Seq | 1.9 GB |
| SRR21594702_GSM6586848 | RNA-Seq | 2.1 GB |
| SRR21594703_GSM6586847 | RNA-Seq | 6.5 GB |
| SRR21594704_GSM6586846 | RNA-Seq | 2.6 GB |
| SRR21594705_GSM6586845 | RNA-Seq | 2.9 GB |
| SRR21594706_GSM6586844 | RNA-Seq | 4.5 GB |
| SRR21594707_GSM6586843 | RNA-Seq | 6.2 GB |
| SRR21594708_GSM6586842 | RNA-Seq | 3.2 GB |
| SRR21594709_GSM6586841 | RNA-Seq | 2.4 GB |
| SRR21594710_GSM6586840 | RNA-Seq | 2.5 GB |
| SRR21594711_GSM6586839 | RNA-Seq | 1.7 GB |
Areas of H3K27 tri-methylation in CD8+ T cells from the spleens of LCMV-Armstrong or LCMV-Clone 13 infected mice
Mus musculus
12 data files
| File | Type | Size |
|---|---|---|
| 10-H3K27me3_C2_S45_L002_R1_001.fastq.gz | ChIP-Seq | 2.0 GB |
| 12-IgG_C2_S47_L002_R1_001.fastq.gz | ChIP-Seq | 3.9 GB |
| 2-H3K4me3_A2_S37_L002_R1_001.fastq.gz | ChIP-Seq | 2.9 GB |
| 4-H3K27me3_A2_S39_L002_R1_001.fastq.gz | ChIP-Seq | 6.6 GB |
| 6-IgG_A2_S41_L002_R1_001.fastq.gz | ChIP-Seq | 5.4 GB |
| 8-H3K4me3_C2_S43_L002_R1_001.fastq.gz | ChIP-Seq | 2.4 GB |
| SRR21594540_GSM6586826 | ChIP-Seq | 3.9 GB |
| SRR21594541_GSM6586825 | ChIP-Seq | 5.4 GB |
| SRR21594542_GSM6586824 | ChIP-Seq | 2.4 GB |
| SRR21594543_GSM6586823 | ChIP-Seq | 2.9 GB |
| SRR21594544_GSM6586822 | ChIP-Seq | 2.0 GB |
| SRR21594545_GSM6586821 | ChIP-Seq | 6.6 GB |
Open chromatin regions at the single cell level of CD8+ T cells from the spleens of LCMV-Armstrong or LCMV-Clone 13 infected mice
Mus musculus
16 data files
| File | Type | Size |
|---|---|---|
| Div1_Arm_Spl_1_S17_L001_R1_001.fastq.gz | ATAC-seq | 4.1 GB |
| Div1_Arm_Spl_2_S18_L001_R1_001.fastq.gz | ATAC-seq | 4.8 GB |
| Div1_Arm_Spl_3_S19_L001_R1_001.fastq.gz | ATAC-seq | 1.5 GB |
| Div1_Arm_Spl_4_S20_L001_R1_001.fastq.gz | ATAC-seq | 3.9 GB |
| Div1_Cl13_Spl_1_S21_L001_R1_001.fastq.gz | ATAC-seq | 4.4 GB |
| Div1_Cl13_Spl_2_S22_L001_R1_001.fastq.gz | ATAC-seq | 4.2 GB |
| Div1_Cl13_Spl_3_S23_L001_R1_001.fastq.gz | ATAC-seq | 4.3 GB |
| Div1_Cl13_Spl_4_S24_L001_R1_001.fastq.gz | ATAC-seq | 5.1 GB |
| SRR21594569_GSM6586834 | ATAC-seq | 4.4 GB |
| SRR21594570_GSM6586834 | ATAC-seq | 4.2 GB |
| SRR21594571_GSM6586834 | ATAC-seq | 4.3 GB |
| SRR21594572_GSM6586834 | ATAC-seq | 5.1 GB |
| SRR21594573_GSM6586833 | ATAC-seq | 4.1 GB |
| SRR21594574_GSM6586833 | ATAC-seq | 4.8 GB |
| SRR21594575_GSM6586833 | ATAC-seq | 1.5 GB |
| SRR21594576_GSM6586833 | ATAC-seq | 3.9 GB |
Potentially related datasets 3
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
| Accession | Source | Title |
|---|---|---|
| GSE213469 | GSE · GEO GEO ↗ | Open chromatin regions at the single cell level of CD8+ T cells from the spleens of LCMV-Armstrong or LCMV-Clone 13 … |
| GSE213470 | GSE · GEO GEO ↗ | Gene expression profiles at the single cell level of CD8+ T cells from the spleens of LCMV-Armstrong or LCMV-Clone 13 … |
| GSE213467 | GSE · GEO GEO ↗ | Areas of H3K27 tri-methylation in CD8+ T cells from the spleens of LCMV-Armstrong or LCMV-Clone 13 infected mice |
Analysis pipelines 3
| Pipeline | Assay | Steps | Dataset |
|---|---|---|---|
| GSE213467 ChIP-seq Data Processing geo_data_processing | ChIP-seq | 11 | GSE213467 |
| GSE213469 ATAC-seq Data Processing geo_data_processing | ATAC-seq | 2 | GSE213469 |
| GSE213470 scRNA-seq Data Processing geo_data_processing | scRNA-seq | 2 | GSE213470 |
Funding 12 grants
| Grant | Funder |
|---|---|
| S10 OD026929 | NIH HHS (United States) |
| R01 HG004659 | NHGRI NIH HHS (United States) |
| P30 CA023100 | NCI NIH HHS (United States) |
| R01 AI113923 | NIAID NIH HHS (United States) |
| P30 DK120515 | NIDDK NIH HHS (United States) |
| R01 AI129973 | NIAID NIH HHS (United States) |
| P30 DK063491 | NIDDK NIH HHS (United States) |
| P01 AI132122 | NIAID NIH HHS (United States) |
| I01 CX002396 | CSRD VA (United States) |
| R01 AI123202 | NIAID NIH HHS (United States) |
| I01 BX005106 | BLRD VA (United States) |
| R01 AI145314 | NIAID NIH HHS (United States) |