Landscape of Exhausted Virus-Specific CD8 T Cells in Chronic LCMV Infection

Sandu, Ioana; Cerletti, Dario; Oetiker, Nathalie; Borsa, Mariana; Wagen, Franziska; Sciamanna, Ilaria; Welten, Suzanne P. M.; Stolz, Ugnė; Oxenius, Annette; Claassen, Manfred

doi:10.1016/j.celrep.2020.108078

Cited by 49 publications

(54 citation statements)

References 111 publications

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“…A crucial variable affecting the heterogeneity of T cells is their environment. Sandu et al 47 investigated the diversity of CD8 + T cells in chronic LCMV infection across six different tissues, and defined organ-specific transcriptomic profiles that could be divided into five main functional subtypes. Taking advantage of our reference CD8 + T cell atlas for viral infection, we re-analyzed the data from Sandu et al to investigate if tissue-specific transcriptomic alterations could be detected using our automated ProjecTILs pipeline (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Interpretation of T cell states from single-cell transcriptomics data using reference atlases

Andreatta

Corría-Osorio

Müller³

et al. 2021

Nat Commun

281

266

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Single-cell RNA sequencing (scRNA-seq) has revealed an unprecedented degree of immune cell diversity. However, consistent definition of cell subtypes and cell states across studies and diseases remains a major challenge. Here we generate reference T cell atlases for cancer and viral infection by multi-study integration, and develop ProjecTILs, an algorithm for reference atlas projection. In contrast to other methods, ProjecTILs allows not only accurate embedding of new scRNA-seq data into a reference without altering its structure, but also characterizing previously unknown cell states that “deviate” from the reference. ProjecTILs accurately predicts the effects of cell perturbations and identifies gene programs that are altered in different conditions and tissues. A meta-analysis of tumor-infiltrating T cells from several cohorts reveals a strong conservation of T cell subtypes between human and mouse, providing a consistent basis to describe T cell heterogeneity across studies, diseases, and species.

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Section: Resultsmentioning

confidence: 99%

“…Single-cell expression matrices for LCMV-specific CD8 + T cells in multiple tissues (Fig. 5 ) were kindly provided by the authors 47 ; raw single-cell data are also available at ENA under accession code PRJEB36998 .…”

mentioning

confidence: 99%

Interpretation of T cell states from single-cell transcriptomics data using reference atlases

Andreatta

Corría-Osorio

Müller³

et al. 2021

Nat Commun

281

266

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“…The expression of inhibitory receptors is thus not a simple on/off FOXO1 switch but requires integration of multiple signals with evidence that the oxygen environment is particularly important (59). In terms of T cell exhaustion and the ability of PI3K p110d to control CD8 + effector/memory T cells transition then FOXO1 control of Ctla4 and Slamf6 mRNA could be relevant as these two molecules control T cell exhaustion (26,60,61). However, the role of FOXO1 in enforcing T cell quiescence by controlling expression of Tcf7, Klf2 and AP-1 family transcription factors will also be important in regulating the effector/memory versus senescent fate of CD8 + T cells (50).…”

Section: Discussionmentioning

confidence: 99%

Phosphoinositide 3-Kinase p110 Delta Differentially Restrains and Directs Naïve Versus Effector CD8+ T Cell Transcriptional Programs

et al. 2021

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Phosphoinositide 3-kinase p110 delta (PI3K p110δ) is pivotal for CD8+ T cell immune responses. The current study explores PI3K p110δ induction and repression of antigen receptor and cytokine regulated programs to inform how PI3K p110δ directs CD8+ T cell fate. The studies force a revision of the concept that PI3K p110δ controls metabolic pathways in T cells and reveal major differences in PI3K p110δ regulated transcriptional programs between naïve and effector cytotoxic T cells (CTL). These differences include differential control of the expression of cytolytic effector molecules and costimulatory receptors. Key insights from the work include that PI3K p110δ signalling pathways repress expression of the critical inhibitory receptors CTLA4 and SLAMF6 in CTL. Moreover, in both naïve and effector T cells the dominant role for PI3K p110δ is to restrain the production of the chemokines that orchestrate communication between adaptive and innate immune cells. The study provides a comprehensive resource for understanding how PI3K p110δ uses multiple processes mediated by Protein Kinase B/AKT, FOXO1 dependent and independent mechanisms and mitogen-activated protein kinases (MAPK) to direct CD8+ T cell fate.

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“…Hence, reference construction requires application of one of many recently developed single-cell integration algorithms 13–19 . Our group previously developed Harmony 15 , a fast, accurate, and well-reviewed method 20 that is able to explicitly model complex study design, a property that makes it suitable for integrating complex datasets into reference atlases 21–24 . Once such atlases are constructed, powerful mapping algorithms will make it possible to rapidly and reproducibly map new single-cell datasets onto the reference and automatically annotate them by transferring information from nearby reference cells.…”

Section: Introductionmentioning

confidence: 99%

“…Hence, reference construction requires application of one of many recently developed single-cell integration algorithms [13][14][15][16][17][18][19] . Our group previously developed Harmony 15 , a fast, accurate, and well-reviewed method 20 that is able to explicitly model complex study design, a property that makes it suitable for integrating complex datasets into reference atlases [21][22][23][24] .…”

Section: Introductionmentioning

confidence: 99%

Efficient and precise single-cell reference atlas mapping with Symphony

Kang

Nathan

Zhang

et al. 2020

Preprint

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Recent advances in single-cell technologies and integration algorithms make it possible to construct large, comprehensive reference atlases from multiple datasets encompassing many donors, studies, disease states, and sequencing platforms. Much like mapping sequencing reads to a reference genome, it is essential to be able to map new query cells onto complex, multimillion-cell reference atlases to rapidly identify relevant cell states and phenotypes. We present Symphony, a novel algorithm for building compressed, integrated reference atlases of ≥106 cells and enabling efficient query mapping within seconds. Based on a linear mixture model framework, Symphony precisely localizes query cells within a low-dimensional reference embedding without the need to reintegrate the reference cells, facilitating the downstream transfer of many types of reference-defined annotations to the query cells. We demonstrate the power of Symphony by (1) mapping a query containing multiple levels of experimental design to predict pancreatic cell types in human and mouse, (2) localizing query cells along a smooth developmental trajectory of human fetal liver hematopoiesis, and (3) harnessing a multimodal CITE-seq reference atlas to infer query surface protein expression in memory T cells. Symphony will enable the sharing of comprehensive integrated reference atlases in a convenient, portable format that powers fast, reproducible querying and downstream analyses.

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Landscape of Exhausted Virus-Specific CD8 T Cells in Chronic LCMV Infection

Cited by 49 publications

References 111 publications

Interpretation of T cell states from single-cell transcriptomics data using reference atlases

Interpretation of T cell states from single-cell transcriptomics data using reference atlases

Phosphoinositide 3-Kinase p110 Delta Differentially Restrains and Directs Naïve Versus Effector CD8+ T Cell Transcriptional Programs

Efficient and precise single-cell reference atlas mapping with Symphony

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