Deficiency of stearoyl-CoA desaturase-1 aggravates colitogenic potential of adoptively transferred effector T cells

Stearoyl-CoA desaturase-1 (SCD1) is a lipogenic enzyme involved in the de novo biosynthesis of oleate (C18:1, n9), a major fatty acid in the phospholipids of lipid bilayers of cell membranes. Accordingly, Scd1KO mice display substantially reduced oleate in cell membranes. An altered SCD1 level was observed during intestinal inflammation; however, its role in modulating inflammatory bowel disease remains elusive. Herein, we investigated the colitogenic capacity of Scd1KO effector T cells by employing the adoptive T-cell transfer colitis model. Splenic effector T cells (CD4+CD25−) from age- and sex-matched wild-type (WT) and Scd1KO mice were isolated by FACS and intraperitoneally administered to Rag1KO mice, which were monitored for the development of colitis. At day 60 postcell transfer, Rag1KO mice that received Scd1KO CD4+CD25− T cells displayed accelerated and exacerbated colitis than mice receiving WT CD4+CD25− T cells. Intriguingly, Scd1KO CD4+CD25− T cells display augmented inflammatory cytokine profile and cellular membrane fluidity with a concomitant increase in proinflammatory saturated fatty acids, which we postulate to potentially underlie their augmented colitogenic potential.

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Direct and indirect antigen presentation lead to deletion of donor-specific T cells after in utero hematopoietic cell transplantation in mice

Blood ◽

10.1182/blood-2012-10-463174 ◽

2013 ◽

Vol 121 (22) ◽

pp. 4595-4602 ◽

Cited By ~ 29

Author(s):

Amar Nijagal ◽

Chris Derderian ◽

Tom Le ◽

Erin Jarvis ◽

Linda Nguyen ◽

...

Keyword(s):

T Cells ◽

Antigen Presentation ◽

Cell Transplantation ◽

Hematopoietic Cell Transplantation ◽

De Novo ◽

Tolerance Induction ◽

In Utero ◽

Effector T Cells ◽

Hematopoietic Cell ◽

Key Points

Key Points Tolerance induction after in utero hematopoietic cell transplantation involves both direct and indirect antigen presentation. Tolerance is achieved by deletion of effector T cells, which results in Treg enrichment without de novo Treg induction.

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S1e2-8 Micropatterned composite membranes of polymerized and fluid lipid bilayers as a versatile model cellular membrane(S1-e2: "New Biomembrane Model Systems, Giant Liposomes and Supported Planar Bilayers, for Probing Biomembrane Structure and Function, and Creation of De Novo Functional Membrane System",Symposia,Abstract,Meeting Program of EABS & BSJ 2006)

Seibutsu Butsuri ◽

10.2142/biophys.46.s118_4 ◽

2006 ◽

Vol 46 (supplement2) ◽

pp. S118

Author(s):

Kenichi Morigaki

Keyword(s):

Lipid Bilayers ◽

De Novo ◽

Composite Membranes ◽

Membrane System ◽

Cellular Membrane ◽

Model Systems ◽

Planar Bilayers ◽

Meeting Program ◽

Functional Membrane ◽

And Function

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Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis

Mucosal Immunology ◽

10.1038/s41385-021-00423-5 ◽

2021 ◽

Author(s):

Maria E. Joosse ◽

Fabienne Charbit-Henrion ◽

Remy Boisgard ◽

Rolien C. Raatgeep ◽

Dicky J. Lindenbergh-Kortleve ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Early Onset ◽

Intestinal Inflammation ◽

De Novo ◽

Cell Receptor ◽

Effector Memory ◽

Colonic Disease ◽

Cd25 Expression

AbstractSingle genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3+, and Foxp3neg CD4+ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4+ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4+ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.

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CXCL10+ peripheral activation niches couple preferred sites of Th1 entry with optimal APC encounter

10.1101/2020.10.04.324525 ◽

2020 ◽

Author(s):

Hen Prizant ◽

Nilesh Patil ◽

Seble Negatu ◽

Alexander McGurk ◽

Scott A. Leddon ◽

...

Keyword(s):

T Cells ◽

T Cell Activation ◽

Hot Spots ◽

Cell Activation ◽

De Novo ◽

Effector T Cells ◽

Mhc Ii ◽

Pathogen Control ◽

Antigen Presenting ◽

Peripheral Activation

SUMMARYCorrect positioning of T cells within infected tissues is critical for T cell activation and pathogen control. Upon tissue entry, effector T cells must efficiently locate antigen presenting cells (APC) for peripheral activation. We reveal that tissue entry and initial peripheral activation of Th1 effector T cells are tightly linked to perivascular positioning of chemokine-expressing APCs. Dermal inflammation induced tissue-wide de novo generation of discrete perivascular CXCL10+ cell clusters, enriched for CD11c+MHC-II+ monocyte-derived dendritic cells. These chemokine clusters were ‘hot spots’ for both Th1 extravasation and activation in the inflamed skin. CXCR3-dependent Th1 localization to the cluster micro-environment prolonged T-APC interactions and boosted function. Both the frequency and range of these clusters were enhanced via a Th1-intrinsic, IFNγ-dependent positive feedback loop. Thus, the perivascular CXCL10+ clusters act as initial peripheral activation niches, optimizing controlled activation broadly throughout the tissue by coupling Th1 tissue entry with enhanced opportunities for Th1-APC encounter.

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Epigenetic Programming during thymic development sets the stage for optimal function in effector T cells via DNA demethylation

10.1101/2021.05.03.442517 ◽

2021 ◽

Author(s):

Athmane Teghanemt ◽

Priyanjali Pulipati ◽

Kenneth Day ◽

Matthew S. Yorek ◽

Ren Yi ◽

...

Keyword(s):

Dna Methylation ◽

T Cells ◽

De Novo ◽

Regulatory Elements ◽

Effector T Cells ◽

Dna Demethylation ◽

Effector Cells ◽

Thymic Development ◽

Repressive Effect ◽

Stimulus Responsive

The repressive effect of DNA methylation at promoters is well-known. However, its role within conserved sequences in intragenic and intergenic regions is less clear. Using Cd4 as a model gene, here we show that DNA methylation regulates the function of stimulus-responsive regulatory elements in effector T cells. Two cis-elements orchestrate intra-and intergenic DNA demethylation of the Cd4 gene during thymic development, which in turn licenses a stimulusresponsive element, E4a, for its later function in effector cells. Deficiency in DNA demethylation leads to impaired E4a function, reduced H3K4me3 promoter levels and an inability to repel de novo DNA methylation during replication, ultimately leading to gene silencing. This physiological reduction in CD4 expression leads to a defect in Th1 polarization during cutaneous Leishmaniasis. Similar patterns of regulation were observed in a broad number of genes, highlighting an essential role for DNA demethylation during thymic development in modulating the function of stimulus-responsive elements.

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Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell–stimulated T cells yet preserves immunity to recall antigen

Blood ◽

10.1182/blood-2011-06-363408 ◽

2011 ◽

Vol 118 (19) ◽

pp. 5330-5339 ◽

Cited By ~ 59

Author(s):

Brian C. Betts ◽

Omar Abdel-Wahab ◽

Shane A. Curran ◽

Erin T. St Angelo ◽

Priya Koppikar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Dendritic Cell ◽

De Novo ◽

Effector T Cells ◽

Janus Kinase ◽

Effector Memory ◽

Janus Kinase 2 ◽

Immune Impairment ◽

Jak2 Inhibition

Abstract Janus kinase-2 (JAK2) conveys receptor-binding signals by several inflammatory cytokines, including IL-6, via phosphorylation of signal transducer and activator of transcription 3 (STAT3). We demonstrate that selective JAK2 inhibition by TG101348 during initial encounters between human T cells and allogeneic monocyte-derived dendritic cells induces durable, profound, and specific T-cell tolerance upon reexposure to the same alloantigens. Subsequent responses by nonalloreactive T cells to stimulation de novo by a pathogenic nominal antigen remain intact. TG101348 also suppresses primed T-cell responses when present only during alloantigen restimulation. TG101348 ablates IL-6/JAK2–mediated phosphorylation of STAT3, but has no off-target effects on IL-2 or IL-15/JAK3/pSTAT5-dependent signaling, which sustain the responses of regulatory T cells (Tregs) and other effector T cells. JAK2 inhibition preserves Treg numbers and thereby enhances the ratio of CD4+ Tregs to CD8+CD25+ effector T cells in favor of Tregs. JAK2 inhibition also reduces the production of IL-6 and TNF-α in allogeneic MLRs, impairing the activation of central and effector memory T cells as well as the expansion of responder Th1 and Th17 cells. While we have reported the limitations of isolated IL-6R-α inhibition on dendritic cell–stimulated alloreactivity, we demonstrate here that JAK2 represents a relevant biologic target for controlling GVHD or allograft rejection without broader immune impairment.

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