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Heterogenous Populations of Tissue-Resident CD8<sup>+</sup> T Cells Are Generated in Response to Infection and Malignancy.

J Justin Milner, Clara Toma, Zhaoren He, Nadia S Kurd, Quynh P Nguyen, Bryan McDonald, Lauren Quezada, Christella E Widjaja, Deborah A Witherden, John T Crowl, Laura A Shaw, Gene W Yeo, John T Chang, Kyla D Omilusik, Ananda W Goldrath

Immunity · 2020 · Vol. 52 (5) · pp. 808-824.e7

PubMed ↗ DOI ↗ PMC full text ↗

Abstract

Tissue-resident memory CD8<sup>+</sup> T cells (Trm) provide host protection through continuous surveillance of non-lymphoid tissues. Using single-cell RNA-sequencing (scRNA-seq) and genetic reporter mice, we identified discrete lineages of intestinal antigen-specific CD8<sup>+</sup> T cells, including a Blimp1<sup>hi</sup>Id3<sup>lo</sup> tissue-resident effector cell population most prominent in the early phase of acute viral and bacterial infections and a molecularly distinct Blimp1<sup>lo</sup>Id3<sup>hi</sup> tissue-resident memory population that subsequently accumulated at later infection time points. These Trm populations exhibited distinct cytokine production, secondary memory potential, and transcriptional programs including differential roles for transcriptional regulators Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal Trm. Extending our analysis to malignant tissue, we also identified discrete populations of effector-like and memory-like CD8<sup>+</sup> T cell populations with tissue-resident gene-expression signatures that shared features of terminally exhausted and progenitor-exhausted T cells, respectively. Our findings provide insight into the development and functional heterogeneity of Trm cells, which has implications for enhancing vaccination and immunotherapy approaches.

Linked datasets 5

GSE147081 GSE · via ncbi_elink
GEO ↗

Single Cell RNA-Seq of CD8+ T cell subsets responding to tumor

Mus musculus

32 data files
FileTypeSize
SRR11318011_GSM4416530 RNA-Seq 906.0 MB
SRR11318012_GSM4416530 RNA-Seq 382.0 MB
SRR11318013_GSM4416530 RNA-Seq 1.3 GB
SRR11318014_GSM4416530 RNA-Seq 1.4 GB
SRR11318015_GSM4416531 RNA-Seq 1.3 GB
SRR11318016_GSM4416531 RNA-Seq 901.0 MB
SRR11318017_GSM4416531 RNA-Seq 1.2 GB
SRR11318018_GSM4416531 RNA-Seq 843.0 MB
SRR11318019_GSM4416532 RNA-Seq 1.2 GB
SRR11318020_GSM4416532 RNA-Seq 836.0 MB
SRR11318021_GSM4416532 RNA-Seq 1.4 GB
SRR11318022_GSM4416532 RNA-Seq 970.0 MB
SRR11318023_GSM4416533 RNA-Seq 1.2 GB
SRR11318024_GSM4416533 RNA-Seq 1.6 GB
SRR11318025_GSM4416533 RNA-Seq 1.3 GB
SRR11318026_GSM4416533 RNA-Seq 875.0 MB
TIL-Try3Spleen1_S10_L005_R1_001.fastq.gz RNA-Seq 906.5 MB
TIL-Try3Spleen1_S11_L005_R1_001.fastq.gz RNA-Seq 382.3 MB
TIL-Try3Spleen1_S12_L005_R1_001.fastq.gz RNA-Seq 1.3 GB
TIL-Try3Spleen1_S9_L005_R1_001.fastq.gz RNA-Seq 1.4 GB
TIL-Try3Spleen2_S13_L005_R1_001.fastq.gz RNA-Seq 1.3 GB
TIL-Try3Spleen2_S14_L005_R1_001.fastq.gz RNA-Seq 901.4 MB
TIL-Try3Spleen2_S15_L005_R1_001.fastq.gz RNA-Seq 1.2 GB
TIL-Try3Spleen2_S16_L005_R1_001.fastq.gz RNA-Seq 843.8 MB
TIL-Try3TIL1_S1_L005_R1_001.fastq.gz RNA-Seq 1.2 GB
TIL-Try3TIL1_S2_L005_R1_001.fastq.gz RNA-Seq 836.4 MB
TIL-Try3TIL1_S3_L005_R1_001.fastq.gz RNA-Seq 1.4 GB
TIL-Try3TIL1_S4_L005_R1_001.fastq.gz RNA-Seq 970.7 MB
TIL-Try3TIL2_S5_L005_R1_001.fastq.gz RNA-Seq 1.2 GB
TIL-Try3TIL2_S6_L005_R1_001.fastq.gz RNA-Seq 1.6 GB
TIL-Try3TIL2_S7_L005_R1_001.fastq.gz RNA-Seq 1.3 GB
TIL-Try3TIL2_S8_L005_R1_001.fastq.gz RNA-Seq 875.6 MB
GSE147080 GSE · via ncbi_elink
GEO ↗

RNA-Seq of CD8+ T cell subsets during LCMV infection II

Mus musculus

16 data files
FileTypeSize
000008565169_A10.R1.fastq.gz RNA-Seq 248.3 MB
000008565169_B10.R1.fastq.gz RNA-Seq 251.0 MB
000008565169_C10.R1.fastq.gz RNA-Seq 192.7 MB
000008565169_D10.R1.fastq.gz RNA-Seq 236.6 MB
000008565169_G09.R1.fastq.gz RNA-Seq 270.7 MB
000008565169_G10.R1.fastq.gz RNA-Seq 230.5 MB
000008565169_H09.R1.fastq.gz RNA-Seq 234.0 MB
000008565169_H10.R1.fastq.gz RNA-Seq 225.8 MB
SRR11317989_GSM4416522 RNA-Seq 270.0 MB
SRR11317990_GSM4416523 RNA-Seq 234.0 MB
SRR11317991_GSM4416524 RNA-Seq 248.0 MB
SRR11317992_GSM4416525 RNA-Seq 251.0 MB
SRR11317993_GSM4416526 RNA-Seq 192.0 MB
SRR11317994_GSM4416527 RNA-Seq 236.0 MB
SRR11317995_GSM4416528 RNA-Seq 230.0 MB
SRR11317996_GSM4416529 RNA-Seq 225.0 MB
GSE147502 GSE · via ncbi_elink
GEO ↗

Heterogeneity of tissue-resident CD8+ T cells in response to infection and malignancy

Mus musculus

GSE147263 GSE · via ncbi_elink
GEO ↗

RNA-Seq of CD8+ T cell subsets in B16-GP33 tumor

Mus musculus

24 data files
FileTypeSize
SK-3L4G_G10.R1.fastq.gz RNA-Seq 360.6 MB
SK-3L4G_G11.R1.fastq.gz RNA-Seq 276.8 MB
SK-3L4G_G12.R1.fastq.gz RNA-Seq 308.3 MB
SK-3L4G_G2.R1.fastq.gz RNA-Seq 311.4 MB
SK-3L4G_G3.R1.fastq.gz RNA-Seq 300.8 MB
SK-3L4G_G4.R1.fastq.gz RNA-Seq 320.5 MB
SK-3L4G_G5.R1.fastq.gz RNA-Seq 320.0 MB
SK-3L4G_G6.R1.fastq.gz RNA-Seq 323.3 MB
SK-3L4G_G7.R1.fastq.gz RNA-Seq 337.8 MB
SK-3L4G_G8.R1.fastq.gz RNA-Seq 272.0 MB
SK-3L4G_G9.R1.fastq.gz RNA-Seq 293.4 MB
SK-3L4G_H1.R1.fastq.gz RNA-Seq 376.4 MB
SRR11357341_GSM4422856 RNA-Seq 360.0 MB
SRR11357342_GSM4422857 RNA-Seq 276.0 MB
SRR11357343_GSM4422858 RNA-Seq 272.0 MB
SRR11357344_GSM4422859 RNA-Seq 293.0 MB
SRR11357345_GSM4422860 RNA-Seq 308.0 MB
SRR11357346_GSM4422861 RNA-Seq 376.0 MB
SRR11357347_GSM4422862 RNA-Seq 320.0 MB
SRR11357348_GSM4422863 RNA-Seq 300.0 MB
SRR11357349_GSM4422864 RNA-Seq 311.0 MB
SRR11357350_GSM4422865 RNA-Seq 320.0 MB
SRR11357351_GSM4422866 RNA-Seq 323.0 MB
SRR11357352_GSM4422867 RNA-Seq 337.0 MB
GSE147021 GSE · via ncbi_elink
GEO ↗

RNA-Seq of CD8+ T cell subsets during LCMV infection I

Mus musculus

54 data files
FileTypeSize
000008565169_E11.R1.fastq.gz RNA-Seq 239.0 MB
000008565169_F11.R1.fastq.gz RNA-Seq 236.9 MB
000008565169_G11.R1.fastq.gz RNA-Seq 157.0 MB
000008565169_H11.R1.fastq.gz RNA-Seq 168.0 MB
000008570169_A01.R1.fastq.gz RNA-Seq 145.7 MB
000008570169_A02.R1.fastq.gz RNA-Seq 179.7 MB
000008570169_A03.R1.fastq.gz RNA-Seq 197.5 MB
000008570169_A04.R1.fastq.gz RNA-Seq 211.8 MB
000008570169_B01.R1.fastq.gz RNA-Seq 229.8 MB
000008570169_B02.R1.fastq.gz RNA-Seq 191.3 MB
000008570169_B03.R1.fastq.gz RNA-Seq 234.2 MB
000008570169_B04.R1.fastq.gz RNA-Seq 185.5 MB
000008570169_C02.R1.fastq.gz RNA-Seq 212.0 MB
000008570169_C04.R1.fastq.gz RNA-Seq 192.9 MB
000008570169_D02.R1.fastq.gz RNA-Seq 206.6 MB
000008570169_D04.R1.fastq.gz RNA-Seq 163.2 MB
000008570169_E01.R1.fastq.gz RNA-Seq 308.4 MB
000008570169_E02.R1.fastq.gz RNA-Seq 205.6 MB
000008570169_E03.R1.fastq.gz RNA-Seq 247.3 MB
000008570169_F01.R1.fastq.gz RNA-Seq 310.3 MB
000008570169_F02.R1.fastq.gz RNA-Seq 240.1 MB
000008570169_F03.R1.fastq.gz RNA-Seq 271.7 MB
000008570169_G02.R1.fastq.gz RNA-Seq 244.2 MB
000008570169_G03.R1.fastq.gz RNA-Seq 301.5 MB
000008570169_H01.R1.fastq.gz RNA-Seq 181.4 MB
000008570169_H02.R1.fastq.gz RNA-Seq 200.3 MB
000008570169_H03.R1.fastq.gz RNA-Seq 211.1 MB
SRR11356436_GSM4412318 RNA-Seq 239.0 MB
SRR11356437_GSM4412319 RNA-Seq 236.0 MB
SRR11356438_GSM4412320 RNA-Seq 157.0 MB
SRR11356439_GSM4412321 RNA-Seq 168.0 MB
SRR11356440_GSM4412322 RNA-Seq 145.0 MB
SRR11356441_GSM4412323 RNA-Seq 229.0 MB
SRR11356442_GSM4412330 RNA-Seq 308.0 MB
SRR11356443_GSM4412331 RNA-Seq 310.0 MB
SRR11356444_GSM4412333 RNA-Seq 181.0 MB
SRR11356445_GSM4412334 RNA-Seq 179.0 MB
SRR11356446_GSM4412335 RNA-Seq 191.0 MB
SRR11356447_GSM4412336 RNA-Seq 212.0 MB
SRR11356448_GSM4412337 RNA-Seq 206.0 MB
SRR11356449_GSM4412338 RNA-Seq 205.0 MB
SRR11356450_GSM4412339 RNA-Seq 240.0 MB
SRR11356451_GSM4412340 RNA-Seq 244.0 MB
SRR11356452_GSM4412341 RNA-Seq 200.0 MB
SRR11356453_GSM4412342 RNA-Seq 197.0 MB
SRR11356454_GSM4412343 RNA-Seq 234.0 MB
SRR11356455_GSM4412346 RNA-Seq 247.0 MB
SRR11356456_GSM4412347 RNA-Seq 271.0 MB
SRR11356457_GSM4412348 RNA-Seq 301.0 MB
SRR11356458_GSM4412349 RNA-Seq 211.0 MB
SRR11356459_GSM4412350 RNA-Seq 211.0 MB
SRR11356460_GSM4412351 RNA-Seq 185.0 MB
SRR11356461_GSM4412352 RNA-Seq 192.0 MB
SRR11356462_GSM4412353 RNA-Seq 163.0 MB

Potentially related datasets 5

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
GSE131847 GSE · GEO GEO ↗ Molecular determinants and heterogeneity of circulating and tissue-resident memory CD8+ T lymphocytes revealed by single-cell RNA sequencing
GSE84105 GSE · GEO GEO ↗ Defining memory-like CD8 T cells that respond to PD-1 therapy in chronic viral infection
GSE9650 GSE · GEO GEO ↗ Chronic viral infection of naive, effector, memory and exhausted virus-specific CD8 T cells
GSE122713 GSE · GEO GEO ↗ scRNA-seq, bulk RNA-seq, and ATAC-seq data from progenitor exhausted and terminally exhausted CD8+ T cells from tumors and chronic viral …
GSE147502 GSE · GEO GEO ↗ Heterogeneity of tissue-resident CD8+ T cells in response to infection and malignancy

Analysis pipelines 8

Pipeline Assay Steps Dataset
GSE122713 RNA-seq Data Processing geo_data_processing RNA-seq 3 GSE122713
GSE147021 RNA-seq Data Processing geo_data_processing RNA-seq 3 GSE147021
GSE147080 RNA-seq Data Processing geo_data_processing RNA-seq 3 GSE147080
GSE147081 RNA-seq Data Processing geo_data_processing RNA-seq 5 GSE147081
GSE147263 RNA-seq Data Processing geo_data_processing RNA-seq 3 GSE147263
GSE147502 Data Processing geo_data_processing — 3 GSE147502
GSE84105 Data Processing geo_data_processing — 1 GSE84105
GSE9650 Microarray Data Processing geo_data_processing Microarray 1 GSE9650
Funding 5 grants
Grant Funder
P30 CA023100 NCI NIH HHS (United States)
P30 DK063491 NIDDK NIH HHS (United States)
P01 AI132122 NIAID NIH HHS (United States)
R37 AI067545 NIAID NIH HHS (United States)
K99 CA234430 NCI NIH HHS (United States)