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Article ; Online: Characterization of human CD4

Pulvirenti, Nadia / Silvetri, Ylenia / Clemente, Francesca / Bosotti, Roberto / Carelli, Elena / Moschetti, Giorgia / Gruarin, Paola / Vasco, Chiara / Crosti, Maria Cristina / Sarnicola, Maria Lucia / Valenti, Luca / Prati, Daniele / Abrignani, Sergio / Geginat, Jens

European journal of immunology

2024 Volume 54, Issue 4, Page(s) e2350675

Abstract: ... Human ... ...

Abstract	Human CD4
MeSH term(s)	Humans ; Interleukin-10 ; T-Lymphocyte Subsets ; T-Lymphocytes, Regulatory ; CD4-Positive T-Lymphocytes ; Th1 Cells ; Cell Differentiation ; T-Box Domain Proteins/genetics
Chemical Substances	Interleukin-10 (130068-27-8) ; EOMES protein, human ; T-Box Domain Proteins
Language	English
Publishing date	2024-02-23
Publishing country	Germany
Document type	Journal Article
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202350675
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Article ; Online: SARS-COV-2 specific t-cells in patients with thyroid disorders related to COVID-19 are enriched in the thyroid and acquire a tissue-resident memory phenotype.

Clinical immunology (Orlando, Fla.)

2023 Volume 254, Page(s) 109684

Abstract: Background: SARS-CoV-2 infections have been associated with the onset of thyroid disorders like classic subacute thyroiditis (SAT) or atypical SAT upon severe COVID disease (COV-A-SAT). Little is known about thyroid anti-viral immune responses.: ... ...

Abstract	Background: SARS-CoV-2 infections have been associated with the onset of thyroid disorders like classic subacute thyroiditis (SAT) or atypical SAT upon severe COVID disease (COV-A-SAT). Little is known about thyroid anti-viral immune responses. Objectives: To define the role of T-cells in COV-A-SAT. Methods: T-cells from COV-A-SAT patients were analyzed by multi-dimensional flow cytometry, UMAP and DiffusionMap dimensionality reduction and FlowSOM clustering. T-cells from COVID-naïve healthy donors, patients with autoimmune thyroiditis (ATD) and with SAT following COVID vaccination were analyzed as controls. T-cells were analyzed four and eight months post-infection in peripheral blood and in thyroid specimen obtained by ultrasound-guided fine needle aspiration. SARS-COV2-specific T-cells were identified by cytokine production induced by SARS-COV2-derived peptides and with COVID peptide-loaded HLA multimers after HLA haplotyping. Results: COV-A-SAT was associated with HLA-DRB113 and HLA-B57. COV-A-SAT patients contained activated Th1- and cytotoxic CD4+ and CD8+ effector cells four months post-infection, which acquired a quiescent memory phenotype after eight months. Anti-SARS-CoV-2-specific T-cell responses were readily detectable in peripheral blood four months post-infection, but were reduced after eight months. CD4+ and CD8+ tissue-resident memory cells (TRM) were present in the thyroid, and circulating CXCR3+T-cells identified as their putative precursors. SARS-CoV-2-specific T-cells were enriched in the thyroid, and acquired a TRM phenotype eight months post-infection. Conclusions: The association of COV-A-SAT with specific HLA haplotypes suggests a genetic predisposition and a key role for T-cells. COV-A-SAT is characterized by a prolonged systemic anti-viral effector T-cell response and the late generation of COVID-specific TRM in the thyroid target tissue.
MeSH term(s)	Humans ; Thyroid Gland ; SARS-CoV-2 ; COVID-19 ; RNA, Viral ; Phenotype ; Antibodies
Chemical Substances	RNA, Viral ; Antibodies
Language	English
Publishing date	2023-07-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1459903-x
ISSN	1521-7035 ; 1521-6616
ISSN (online)	1521-7035
ISSN	1521-6616
DOI	10.1016/j.clim.2023.109684
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Article ; Online: An Intestinal Th17 Subset is Associated with Inflammation in Crohn's Disease and Activated by Adherent-invasive Escherichia coli.

Paroni, Moira / Leccese, Gabriella / Ranzani, Valeria / Moschetti, Giorgia / Chiara, Matteo / Perillo, Federica / Ferri, Sara / Clemente, Francesca / Noviello, Daniele / Conforti, Francesco Simone / Ferrero, Stefano / Karnani, Bhavna / Bosotti, Roberto / Vasco, Chiara / Curti, Serena / Crosti, Maria Cristina / Gruarin, Paola / Rossetti, Grazisa / Conte, Maria Pia /

Vecchi, Maurizio / Pagani, Massimiliano / Landini, Paolo / Facciotti, Federica / Abrignani, Sergio / Caprioli, Flavio / Geginat, Jens

Journal of Crohn's & colitis

2023 Volume 17, Issue 12, Page(s) 1988–2001

Abstract: IFNγ-producing ex-Th17 cells ['Th1/17'] were shown to play a key pathogenic role in experimental colitis and are abundant in the intestine. Here, we identified and characterised a novel, potentially colitogenic subset of Th17 cells in the intestine of ... ...

Abstract	IFNγ-producing ex-Th17 cells ['Th1/17'] were shown to play a key pathogenic role in experimental colitis and are abundant in the intestine. Here, we identified and characterised a novel, potentially colitogenic subset of Th17 cells in the intestine of patients with Crohn's disease [CD]. Human Th17 cells expressing CCR5 ['pTh17'] co-expressed T-bet and RORC/γt and produced very high levels of IL-17, together with IFN-γ. They had a gene signature of Th17 effector cells and were distinct from established Th1/17 cells. pTh17 cells, but not Th1/17 cells, were associated with intestinal inflammation in CD, and decreased upon successful anti-TNF therapy with infliximab. Conventional CCR5[-]Th17 cells differentiated to pTh17 cells with IL-23 in vitro. Moreover, anti-IL-23 therapy with risankizumab strongly reduced pTh17 cells in the intestine. Importantly, intestinal pTh17 cells were selectively activated by adherent-invasive Escherichia coli [AIEC], but not by a commensal/probiotic E. coli strain. AIEC induced high levels of IL-23 and RANTES from dendritic cells [DC]. Intestinal CCR5+Th1/17 cells responded instead to cytomegalovirus and were reduced in ulcerative colitis [UC], suggesting an unexpected protective role. In conclusion, we identified an IL-23-inducible subset of human intestinal Th17 cells. pTh17 cells produced high levels of pro-inflammatory cytokines, were selectively associated with intestinal inflammation in CD, and responded to CD-associated AIEC, suggesting a key colitogenic role.
MeSH term(s)	Humans ; Crohn Disease/pathology ; Escherichia coli ; Th17 Cells/pathology ; Tumor Necrosis Factor Inhibitors ; Intestines/pathology ; Inflammation/pathology ; Escherichia coli Infections/complications ; Escherichia coli Infections/pathology ; Interleukin-23 ; Intestinal Mucosa/pathology ; Bacterial Adhesion
Chemical Substances	Tumor Necrosis Factor Inhibitors ; Interleukin-23
Language	English
Publishing date	2023-07-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2390120-2
ISSN	1876-4479 ; 1873-9946
ISSN (online)	1876-4479
ISSN	1873-9946
DOI	10.1093/ecco-jcc/jjad119
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Article ; Online: Ex vivo microRNA and gene expression profiling of human Tr1-like cells suggests a role for miR-92a and -125a in the regulation of EOMES and IL-10R.

De Simone, Marco / Chirichella, Michele / Emming, Stefan / Mazzara, Saveria / Ranzani, Valeria / Gruarin, Paola / Moschetti, Giorgia / Pulvirenti, Nadia / Maglie, Stefano / Vasco, Chiara / Crosti, Maria Cristina / Rossetti, Grazisa / Pagani, Massimiliano / Abrignani, Sergio / Monticelli, Silvia / Geginat, Jens

European journal of immunology

2021 Volume 51, Issue 12, Page(s) 3243–3246

Abstract: Ex vivo gene expression and miRNA profiling of ... ...

Abstract	Ex vivo gene expression and miRNA profiling of Eomes
MeSH term(s)	Gene Expression Profiling ; Humans ; MicroRNAs/immunology ; Receptors, Interleukin-10/immunology ; T-Box Domain Proteins/immunology ; Th1 Cells/immunology
Chemical Substances	EOMES protein, human ; MIRN125 microRNA, human ; MIRN92 microRNA, human ; MicroRNAs ; Receptors, Interleukin-10 ; T-Box Domain Proteins
Language	English
Publishing date	2021-09-28
Publishing country	Germany
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202149315
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Article ; Online: The Translational Machinery of Human CD4

Ricciardi, Sara / Manfrini, Nicola / Alfieri, Roberta / Calamita, Piera / Crosti, Maria Cristina / Gallo, Simone / Müller, Rolf / Pagani, Massimiliano / Abrignani, Sergio / Biffo, Stefano

Cell metabolism

2018 Volume 28, Issue 6, Page(s) 895–906.e5

Abstract: Naive T cells respond to T cell receptor (TCR) activation by leaving quiescence, remodeling metabolism, initiating expansion, and differentiating toward effector T cells. The molecular mechanisms coordinating the naive to effector transition are central ... ...

Abstract	Naive T cells respond to T cell receptor (TCR) activation by leaving quiescence, remodeling metabolism, initiating expansion, and differentiating toward effector T cells. The molecular mechanisms coordinating the naive to effector transition are central to the functioning of the immune system, but remain elusive. Here, we discover that T cells fulfill this transitional process through translational control. Naive cells accumulate untranslated mRNAs encoding for glycolysis and fatty acid synthesis factors and possess a translational machinery poised for immediate protein synthesis. Upon TCR engagement, activation of the translational machinery leads to synthesis of GLUT1 protein to drive glucose entry. Subsequently, translation of ACC1 mRNA completes metabolic reprogramming toward an effector phenotype. Notably, inhibition of the eIF4F complex abrogates lymphocyte metabolic activation and differentiation, suggesting ACC1 to be a key regulatory node. Thus, our results demonstrate that translation is a direct mediator of T cell metabolism and indicate translation factors as targets for novel immunotherapeutic approaches.
MeSH term(s)	Acetyl-CoA Carboxylase/biosynthesis ; CD4-Positive T-Lymphocytes/cytology ; CD4-Positive T-Lymphocytes/metabolism ; Cell Differentiation ; Cell Proliferation ; Eukaryotic Initiation Factor-4F/antagonists & inhibitors ; Fatty Acids/metabolism ; Glucose Transporter Type 1/biosynthesis ; Glycolysis ; Humans ; Lymphocyte Activation ; Protein Biosynthesis ; Receptors, Antigen, T-Cell/metabolism ; T-Lymphocyte Subsets/cytology ; T-Lymphocyte Subsets/metabolism
Chemical Substances	Eukaryotic Initiation Factor-4F ; Fatty Acids ; Glucose Transporter Type 1 ; Receptors, Antigen, T-Cell ; SLC2A1 protein, human ; ACACA protein, human (EC 6.4.1.2) ; Acetyl-CoA Carboxylase (EC 6.4.1.2)
Language	English
Publishing date	2018-09-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2018.08.009
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Article ; Online: The Translational Machinery of Human CD4

Ricciardi, Sara / Manfrini, Nicola / Alfieri, Roberta / Calamita, Piera / Crosti, Maria Cristina / Gallo, Simone / Müller, Rolf / Pagani, Massimiliano / Abrignani, Sergio / Biffo, Stefano

Cell metabolism

2018 Volume 28, Issue 6, Page(s) 961

Language	English
Publishing date	2018-12-05
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2018.09.010
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Article ; Online: IL-10 promotes homeostatic proliferation of human CD8(+) memory T cells and, when produced by CD1c(+) DCs, shapes naive CD8(+) T-cell priming.

Nizzoli, Giulia / Larghi, Paola / Paroni, Moira / Crosti, Maria Cristina / Moro, Monica / Neddermann, Petra / Caprioli, Flavio / Pagani, Massimiliano / De Francesco, Raffaele / Abrignani, Sergio / Geginat, Jens

European journal of immunology

2016 Volume 46, Issue 7, Page(s) 1622–1632

Abstract: IL-10 is an anti-inflammatory cytokine that inhibits maturation and cytokine production of dendritic cells (DCs). Although mature DCs have the unique capacity to prime CD8(+) CTL, IL-10 can promote CTL responses. To understand these paradoxic findings, ... ...

Abstract	IL-10 is an anti-inflammatory cytokine that inhibits maturation and cytokine production of dendritic cells (DCs). Although mature DCs have the unique capacity to prime CD8(+) CTL, IL-10 can promote CTL responses. To understand these paradoxic findings, we analyzed the role of IL-10 produced by human APC subsets in T-cell responses. IL-10 production was restricted to CD1c(+) DCs and CD14(+) monocytes. Interestingly, it was differentially regulated, since R848 induced IL-10 in DCs, but inhibited IL-10 in monocytes. Autocrine IL-10 had only a weak inhibitory effect on DC maturation, cytokine production, and CTL priming with high-affinity peptides. Nevertheless, it completely blocked cross-priming and priming with low-affinity peptides of a self/tumor-antigen. IL-10 also inhibited CD1c(+) DC-induced CD4(+) T-cell priming and enhanced Foxp3 induction, but was insufficient to induce T-cell IL-10 production. CD1c(+) DC-derived IL-10 had also no effect on DC-induced secondary expansions of memory CTL. However, IL-15-driven, TCR-independent proliferation of memory CTL was enhanced by IL-10. We conclude that DC-derived IL-10 selects high-affinity CTL upon priming. Moreover, IL-10 preserves established CTL memory by enhancing IL-15-dependent homeostatic proliferation. These combined effects on CTL priming and memory maintenance provide a plausible mechanism how IL-10 promotes CTL responses in humans.
MeSH term(s)	Antigen Presentation/immunology ; Antigens, CD1/metabolism ; Autocrine Communication/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Cross-Priming/immunology ; Cytokines/metabolism ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Glycoproteins/metabolism ; HLA-A Antigens/immunology ; HLA-A Antigens/metabolism ; Humans ; Immunologic Memory/immunology ; Inflammation Mediators/metabolism ; Interleukin-10/metabolism ; Lymphocyte Activation/immunology ; Monocytes/immunology ; Monocytes/metabolism
Chemical Substances	Antigens, CD1 ; CD1C protein, human ; Cytokines ; Glycoproteins ; HLA-A Antigens ; Inflammation Mediators ; Interleukin-10 (130068-27-8)
Language	English
Publishing date	2016-07
Publishing country	Germany
Document type	Journal Article
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.201546136
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Article ; Online: The Translational Machinery of Human CD4 T Cells Is Poised for Activation and Controls the Switch from Quiescence to Metabolic Remodeling.

Ricciardi, Sara / Manfrini, Nicola / Alfieri, Roberta / Calamita, Piera / Crosti, Maria Cristina / Gallo, Simone / Müller, Rolf / Pagani, Massimiliano / Abrignani, Sergio / Biffo, Stefano

Cell metabolism

2018

Abstract	Naive T cells respond to T cell receptor (TCR) activation by leaving quiescence, remodeling metabolism, initiating expansion, and differentiating toward effector T cells. The molecular mechanisms coordinating the naive to effector transition are central to the functioning of the immune system, but remain elusive. Here, we discover that T cells fulfill this transitional process through translational control. Naive cells accumulate untranslated mRNAs encoding for glycolysis and fatty acid synthesis factors and possess a translational machinery poised for immediate protein synthesis. Upon TCR engagement, activation of the translational machinery leads to synthesis of GLUT1 protein to drive glucose entry. Subsequently, translation of ACC1 mRNA completes metabolic reprogramming toward an effector phenotype. Notably, inhibition of the eIF4F complex abrogates lymphocyte metabolic activation and differentiation, suggesting ACC1 to be a key regulatory node. Thus, our results demonstrate that translation is a direct mediator of T cell metabolism and indicate translation factors as targets for novel immunotherapeutic approaches.
Keywords	ACC1 ; CD4(+) T cell ; GLUT1 ; eIF4E ; eIF6 ; metabolism ; metabolome ; proteome ; transcriptome ; translational control
Subject code	570
Language	English
Publishing date	2018-12-04
Publisher	Elsevier/ Cell Press
Publishing country	de
Document type	Article ; Online
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Article ; Online: Intestinal IFN-γ-producing type 1 regulatory T cells coexpress CCR5 and programmed cell death protein 1 and downregulate IL-10 in the inflamed guts of patients with inflammatory bowel disease.

The Journal of allergy and clinical immunology

2018 Volume 142, Issue 5, Page(s) 1537–1547.e8

Abstract: Background: IL-10 is an anti-inflammatory cytokine required for intestinal immune homeostasis. It mediates suppression of T-cell responses by type 1 regulatory T (T: Objective: We aimed to identify and characterize human intestinal T: Methods: CD4! ...

Abstract	Background: IL-10 is an anti-inflammatory cytokine required for intestinal immune homeostasis. It mediates suppression of T-cell responses by type 1 regulatory T (T Objective: We aimed to identify and characterize human intestinal T Methods: CD4 Results: Intestinal T Conclusions: We provide the first ex vivo characterization of human intestinal T
MeSH term(s)	Adult ; Aged ; Animals ; Cells, Cultured ; Colonic Neoplasms/immunology ; Cytokines/immunology ; Female ; Humans ; Inflammatory Bowel Diseases/immunology ; Intestinal Mucosa/immunology ; Male ; Mice, Inbred C57BL ; Mice, Transgenic ; Middle Aged ; Programmed Cell Death 1 Receptor/immunology ; Receptors, CCR5/immunology ; T-Lymphocytes, Regulatory/immunology ; Young Adult
Chemical Substances	CCR5 protein, human ; Cytokines ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; Receptors, CCR5
Language	English
Publishing date	2018-01-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2017.12.984
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Article ; Online: Extracellular MicroRNA Signature of Human Helper T Cell Subsets in Health and Autoimmunity.

The Journal of biological chemistry

2017 Volume 292, Issue 7, Page(s) 2903–2915

Abstract: Upon T cell receptor stimulation, ... ...

Abstract	Upon T cell receptor stimulation, CD4
MeSH term(s)	Autoimmune Diseases/genetics ; Autoimmune Diseases/immunology ; CD4-Positive T-Lymphocytes/cytology ; CD4-Positive T-Lymphocytes/immunology ; Cells, Cultured ; Etanercept/therapeutic use ; Extracellular Vesicles/metabolism ; Humans ; MicroRNAs/blood ; MicroRNAs/genetics ; Psoriasis/blood ; Psoriasis/drug therapy ; Psoriasis/genetics ; T-Lymphocyte Subsets
Chemical Substances	MicroRNAs ; Etanercept (OP401G7OJC)
Language	English
Publishing date	2017-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M116.769893
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