The Intestine Harbors Functionally Distinct Homeostatic Tissue-Resident and Inflammatory Th17 Cells

Omenetti, Sara; Bussi, Claudio; Metidji, Amina; Iseppon, Andrea; Lee, Sunjae; Tolaini, Mauro; Liu, Ying; Kelly, Gavin; Chakravarty, Probir; Shoaie, Saeed; Gutiérrez, Maximiliano G.; Stockinger, Brigitta

doi:10.1016/j.immuni.2019.05.004

Cited by 255 publications

(224 citation statements)

References 63 publications

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“…TEM or TEMRA cells). This is important given the role of TGF-β in Th17 cell biology, and especially since these cells show substantial diversity in vivo 23 . Our study suggests that cells with high effectorness that infiltrate tissues might start the strong responses to local cytokine environment.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, Th17 cells upregulate TBX21 and IFN-γ in response to Th1polarizing cytokines 22 , and infection-induced Th17 cells from the gut can secrete a variety of inflammatory cytokines, e.g. the Th1 cytokine IFNγ 23 . These observations highlight the remarkable plasticity of CD4+ T cells and suggest that memory cells retain the ability to respond to cytokines.…”

mentioning

confidence: 99%

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Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

Cano-Gamez

Soskic

Roumeliotis

et al. 2019

Preprint

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AbstractNaïve CD4+ T cells coordinate the immune response by acquiring an effector phenotype in response to cytokines. However, the cytokine responses in memory T cells remain largely understudied. We used quantitative proteomics, bulk RNA-seq and single-cell RNA-seq of over 40,000 human naïve and memory CD4+ T cells to generate a detailed map of cytokine-regulated gene expression programs. We demonstrated that cytokine response differs substantially between naïve and memory T cells and showed that memory cells are unable to differentiate into the Th2 phenotype. Moreover, memory T cells acquire a Th17-like phenotype in response to iTreg polarization. At the single-cell level, we demonstrated that T cells form a continuum which progresses from naïve to effector memory T cells. This continuum is accompanied by a gradual increase in the expression levels of chemokines and cytokines and thus represents an effectorness gradient. Finally, we found that T cell cytokine responses are determined by where the cells lie in the effectorness gradient and identified genes whose expression is controlled by cytokines in an effectorness-dependent manner. Our results shed light on the heterogeneity of T cells and their responses to cytokines, provide insight into immune disease inflammation and could inform drug development.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

Cano-Gamez

Soskic

Roumeliotis

et al. 2019

Preprint

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“…For example, IL-6 converts regulatory T (Treg) cells to a pathogenic Th17-like phenotype under arthritic conditions 20 . Furthermore, Th17 cells upregulate TBX21 and IFN-γ in response to Th1-polarizing cytokines 21 , and infection-induced Th17 cells can secrete Th1 cytokines 22 . These observations highlight the plasticity of CD4 + T cells and suggest that memory cells respond to cytokines.…”

mentioning

confidence: 99%

Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

et al. 2020

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Naïve CD4 + T cells coordinate the immune response by acquiring an effector phenotype in response to cytokines. However, the cytokine responses in memory T cells remain largely understudied. Here we use quantitative proteomics, bulk RNA-seq, and single-cell RNA-seq of over 40,000 human naïve and memory CD4 + T cells to show that responses to cytokines differ substantially between these cell types. Memory T cells are unable to differentiate into the Th2 phenotype, and acquire a Th17-like phenotype in response to iTreg polarization. Single-cell analyses show that T cells constitute a transcriptional continuum that progresses from naïve to central and effector memory T cells, forming an effectorness gradient accompanied by an increase in the expression of chemokines and cytokines. Finally, we show that T cell activation and cytokine responses are influenced by the effectorness gradient. Our results illustrate the heterogeneity of T cell responses, furthering our understanding of inflammation.

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“…Multiple cohort studies in IBD patients and gnotobiotic animal experiments have identified specific bacterial families and species that influence dysbiosis-mediated immune dysfunction. Segmented filamentous bacteria (SFB) strongly activate Th17 responses in the small intestine of mice [49,50], although SFB induces non-inflammatory homeostatic Th17 cells rather than infectioninduced inflammatory Th17 [51]. Adherent-invasive Escherichia coli (AIEC) and Citrobacter rodentium induce colitogenic Th1 and Th17 responses in the colon [50,52,53] and oral Klebsiella pneumoniae strains activate Th1 cells and colitis when they ectopically colonize the colon [54].…”

Section: Dysbiosis-associated Mucosal Immune-dysfunction In Ibdmentioning

confidence: 99%

Manipulating resident microbiota to enhance regulatory immune function to treat inflammatory bowel diseases

Mishima

Sartor

2019

J Gastroenterol

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Altered intestinal microbial composition (dysbiosis) and metabolic products activate aggressive mucosal immune responses that mediate inflammatory bowel diseases (IBD). This dysbiosis impairs the function of regulatory immune cells, which normally promote mucosal homeostasis. Normalizing and maintaining regulatory immune cell function by correcting dysbiosis provides a promising approach to treat IBD patients. However, existing microbe-targeted therapies, including antibiotics, prebiotics, probiotics, and fecal microbial transplantation, provide variable outcomes that are not optimal for current clinical application. This review discusses recent progress in understanding the dysbiosis of IBD and the basis for therapeutic restoration of homeostatic immune function by manipulating an individual patient's microbiota composition and function. We believe that identifying more precise therapeutic targets and developing appropriate rapid diagnostic tools will guide more effective and safer microbebased induction and maintenance treatments for IBD patients that can be applied in a personalized manner.

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The Intestine Harbors Functionally Distinct Homeostatic Tissue-Resident and Inflammatory Th17 Cells

Cited by 255 publications

References 63 publications

Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

Single-cell transcriptomics identifies an effectorness gradient shaping the response of CD4+ T cells to cytokines

Manipulating resident microbiota to enhance regulatory immune function to treat inflammatory bowel diseases

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