A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells

Singer, Meromit; Wang, Chao; Cong, Le; Marjanovic, Nemanja D.; Kowalczyk, Monika S.; Zhang, Huiyuan; Nyman, Jackson; Sakuishi, Kaori; Kurtuluş, Sema; Gennert, David; Xia, Junrong; Kwon, John; Nevin, James; Herbst, Rebecca H.; Yanai, Itai; Rozenblatt-Rosen, Orit; Kuchroo, Vijay K.; Regev, Aviv; Anderson, Ana C.

doi:10.1016/j.cell.2016.08.052

Cited by 346 publications

(342 citation statements)

References 38 publications

(88 reference statements)

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“…In addition, several genes encoding products known to promote T cell dysfunction, including intracellular metallothioneins ( Mt1 and Mt2 ), which contribute to T cell dysfunction in mouse tumors, as well as the transcription factor c-Maf ( Maf ) and the receptor for prostaglandin E 2 ( Ptger2 ), which contribute to CD8 + T cell dysfunction in a model of chronic infection with lymphocytic choriomeningitis virus (LCMV) clone 13 (refs. 1,24,25), had higher expression in wild-type CD8 + T cells than in Mir31 −/− CD8 + T cells (Fig. 4a,b).…”

Section: Resultsmentioning

confidence: 92%

“…Delineation of the dysfunction signature of tumor-infiltrating CD8 + T cells at the single-cell level has demonstrated that metallothioneins substantially contribute to T cell dysfunction. Metallothionein-deficient mice have a significantly lower tumor burden and stronger CD8 + T cell function than that of metallothionein-sufficient mice 25 . Both Mt1 and Mt2 (which encode metallothioneins) had higher expression in Mir31 +/+ T cells than in Mir31 −/− T cells.…”

Section: Discussionmentioning

confidence: 91%

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The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

et al. 2017

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During infection, antigen-specific T cells undergo tightly regulated developmental transitions controlled by transcriptional and post-transcriptional regulation of gene expression. We found that the microRNA miR-31 was strongly induced by activation of the T cell antigen receptor (TCR) in a pathway involving calcium and activation of the transcription factor NFAT. During chronic infection with lymphocytic choriomeningitis virus (LCMV) clone 13, miR-31-deficent mice recovered from clinical disease, while wild-type mice continued to show signs of disease. This disease phenotype was explained by the presence of larger numbers of cytokine-secreting LCMV-specific CD8+ T cells in miR-31-deficent mice than in wild-type mice. Mechanistically, miR-31 increased the sensitivity of T cells to type I interferons, which interfered with effector T cell function and increased the expression of several proteins related to T cell dysfunction during chronic infection. These studies identify miR-31 as an important regulator of T cell exhaustion in chronic infection.

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Section: Resultsmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 91%

The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

et al. 2017

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“…Full-length RNA-seq libraries were prepared as previously described 45 and paired-end sequenced (75 bp × 2) with a 150 cycle Nextseq 500 high output V2 kit.…”

Section: Methodsmentioning

confidence: 99%

“…We also did not replace these scores with a statistical comparison of them to randomized signatures selected from a null distribution (in contrast to our other studies 20,45 ). Owing to the varying proliferative responses in our cells, it is difficult to find a true null set of signatures, even after matching genes for dataset-wide mean and variance profiles.…”

Section: Methodsmentioning

confidence: 99%

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

Wallrapp

Riesenfeld

Burkett

et al. 2017

Nature

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Type 2 innate lymphoid cells (ILC2s) both contribute to mucosal homeostasis and initiate pathologic inflammation in allergic asthma. However, the signals that direct ILC2s to promote homeostasis versus inflammation are unclear. To identify such molecular cues, we profiled mouse lung-resident ILCs using single-cell RNA sequencing at steady state and after in vivo stimulation with the alarmin cytokines IL-25 and IL-33. ILC2s were transcriptionally heterogeneous after activation, with subpopulations distinguished by expression of proliferative, homeostatic and effector genes. The neuropeptide receptor Nmur1 was preferentially expressed by ILC2s at steady state and after IL-25 stimulation. Neuromedin U (NMU), the ligand of NMUR1, activated ILC2s in vitro, and in vivo co-administration of NMU with IL-25 strongly amplified allergic inflammation. Loss of NMU–NMUR1 signalling reduced ILC2 frequency and effector function, and altered transcriptional programs following allergen challenge in vivo. Thus, NMUR1 signalling promotes inflammatory ILC2 responses, highlighting the importance of neuro-immune crosstalk in allergic inflammation at mucosal surfaces.

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“…Indeed, the PD-1 + T cells found in the circulation of healthy humans comprise effector-memory T cells [28]. Moreover, we have observed uncoupling of co-inhibitory receptor expression from dysfunctional phenotype in CD8 + tumor-infiltrating lymphocytes (TILs) [24]. Thus, it is not possible to discern the presence of a dysfunctional versus activated T cell state based on the expression of co-inhibitory receptors alone.…”

Section: Molecular Signatures Of T Cell Dysfunctionmentioning

confidence: 99%

Molecular Dissection of CD8 + T-Cell Dysfunction

Wang

Singer

Anderson

2017

Trends in Immunology

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Chronic viral infections and cancer often lead to the emergence of dysfunctional or “exhausted” CD8+ T cells, and the restoration of their functions is currently the focus of therapeutic interventions. Here, we detail recent advances in the annotation of the gene modules and the epigenetic landscape associated with T cell dysfunction. Together with analysis of single-cell transcriptomes, these findings have enabled a deeper and more precise understanding of the transcriptional mechanisms that induce and maintain the dysfunctional state and highlight the heterogeneity of CD8+ T cell phenotypes present in chronically inflamed tissue. We discuss the relevance of these findings for understanding the transcriptional and spatial regulation of dysfunctional T cells and for the design of therapeutics.

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A Distinct Gene Module for Dysfunction Uncoupled from Activation in Tumor-Infiltrating T Cells

Cited by 346 publications

References 38 publications

The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection

The neuropeptide NMU amplifies ILC2-driven allergic lung inflammation

Molecular Dissection of CD8 + T-Cell Dysfunction

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