Induction of IL-22-Producing CD4+ T Cells by Segmented Filamentous Bacteria Independent of Classical Th17 Cells

The intestinal microbiota modulates IL-22 production in the intestine, including the induction of IL-22-producing CD4+ T helper cells. Which specific bacteria are responsible for the induction of these cells is less well understood. Here, we demonstrate through the use of novel gnotobiotic knock-in reporter mice that segmented filamentous bacteria (SFB), which are known for their ability to induce Th17 cells, also induce distinct IL-17A negative CD4+ T cell populations in the intestine. A subset of these cells instead produces IL-22 upon restimulation ex vivo and also during enteric infections. Furthermore, they produce a distinct set of cytokines compared to Th17 cells including the differential expression of IL-17F and IFN-γ. Importantly, genetic models demonstrate that these cells, presumably Th22 cells, develop independently of intestinal Th17 cells. Together, our data identifies that besides Th17, SFB also induces CD4+ T cell populations, which serve as immediate source of IL-22 during intestinal inflammation.

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Dissecting the Heterogeneity in T-Cell Mediated Inflammation in IBD

Cells ◽

10.3390/cells9010110 ◽

2020 ◽

Vol 9 (1) ◽

pp. 110 ◽

Cited By ~ 11

Author(s):

Irma Tindemans ◽

Maria E. Joosse ◽

Janneke N. Samsom

Keyword(s):

T Cell ◽

Intestinal Inflammation ◽

T Cell Responses ◽

Cd4 T Cell ◽

Cell Populations ◽

Disease Course ◽

T Helper ◽

Intestinal Tissue ◽

Cell Responses ◽

Chronic Intestinal Inflammation

Infiltration of the lamina propria by inflammatory CD4+ T-cell populations is a key characteristic of chronic intestinal inflammation. Memory-phenotype CD4+ T-cell frequencies are increased in inflamed intestinal tissue of IBD patients compared to tissue of healthy controls and are associated with disease flares and a more complicated disease course. Therefore, a tightly controlled balance between regulatory and inflammatory CD4+ T-cell populations is crucial to prevent uncontrolled CD4+ T-cell responses and subsequent intestinal tissue damage. While at steady state, T-cells display mainly a regulatory phenotype, increased in Th1, Th2, Th9, Th17, and Th17.1 responses, and reduced Treg and Tr1 responses have all been suggested to play a role in IBD pathophysiology. However, it is highly unlikely that all these responses are altered in each individual patient. With the rapidly expanding plethora of therapeutic options to inhibit inflammatory T-cell responses and stimulate regulatory T-cell responses, a crucial need is emerging for a robust set of immunological assays to predict and monitor therapeutic success at an individual level. Consequently, it is crucial to differentiate dominant inflammatory and regulatory CD4+ T helper responses in patients and relate these to disease course and therapy response. In this review, we provide an overview of how intestinal CD4+ T-cell responses arise, discuss the main phenotypes of CD4+ T helper responses, and review how they are implicated in IBD.

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n3 PUFAs Reduce Mouse CD4+ T-Cell Ex Vivo Polarization into Th17 Cells

Journal of Nutrition ◽

10.3945/jn.113.178178 ◽

2013 ◽

Vol 143 (9) ◽

pp. 1501-1508 ◽

Cited By ~ 26

Author(s):

Jennifer M. Monk ◽

Tim Y. Hou ◽

Harmony F. Turk ◽

David N. McMurray ◽

Robert S. Chapkin

Keyword(s):

T Cell ◽

Th17 Cells ◽

Ex Vivo ◽

Cd4 T Cell

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Faculty Opinions recommendation of Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1021392.288807 ◽

2005 ◽

Author(s):

Alan Houghton

Keyword(s):

T Cell ◽

Dendritic Cell ◽

Inflammatory Mediators ◽

Cell Activation ◽

Cd4 T Cell ◽

Cell Populations ◽

Dendritic Cell Activation ◽

Helper Function

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Dynamic Imaging of IEL-IEC Co-Cultures Allows for Quantification of CD103-Dependent T Cell Migration

International Journal of Molecular Sciences ◽

10.3390/ijms22105148 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5148

Author(s):

Karin Enderle ◽

Martin Dinkel ◽

Eva-Maria Spath ◽

Benjamin Schmid ◽

Sebastian Zundler ◽

...

Keyword(s):

T Cell ◽

Cross Talk ◽

Intestinal Inflammation ◽

Ex Vivo ◽

New Technology ◽

Surface Expression ◽

Intraepithelial Lymphocytes ◽

Dynamic Imaging ◽

The Body ◽

Therapeutic Interventions

Intraepithelial lymphocytes (IEL) are widely distributed within the small intestinal epithelial cell (IEC) layer and represent one of the largest T cell pools of the body. While implicated in the pathogenesis of intestinal inflammation, detailed insight especially into the cellular cross-talk between IELs and IECs is largely missing in part due to lacking methodologies to monitor this interaction. To overcome this shortcoming, we employed and validated a murine IEL-IEC (organoids) ex vivo co-culture model system. Using livecell imaging we established a protocol to visualize and quantify the spatio-temporal migratory behavior of IELs within organoids over time. Applying this methodology, we found that IELs lacking CD103 (i.e., integrin alpha E, ITGAE) surface expression usually functioning as a retention receptor for IELs through binding to E-cadherin (CD324) expressing IECs displayed aberrant mobility and migration patterns. Specifically, CD103 deficiency affected the ability of IELs to migrate and reduced their speed during crawling within organoids. In summary, we report a new technology to monitor and quantitatively assess especially migratory characteristics of IELs communicating with IEC ex vivo. This approach is hence readily applicable to study the effects of targeted therapeutic interventions on IEL-IEC cross-talk.

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Comparison of Lethal and Nonlethal Mouse Models of Orientia tsutsugamushi Infection Reveals T-Cell Population-Associated Cytokine Signatures Correlated with Lethality and Protection

Tropical Medicine and Infectious Disease ◽

10.3390/tropicalmed6030121 ◽

2021 ◽

Vol 6 (3) ◽

pp. 121

Author(s):

Alison Luce-Fedrow ◽

Suchismita Chattopadhyay ◽

Teik-Chye Chan ◽

Gregory Pearson ◽

John B. Patton ◽

...

Keyword(s):

Flow Cytometry ◽

T Cell ◽

Host Response ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

Cell Populations ◽

Murine Models ◽

Orientia Tsutsugamushi ◽

Multicolor Flow Cytometry ◽

Interstrain Difference

The antigenic diversity of Orientia tsutsugamushi as well as the interstrain difference(s) associated with virulence in mice impose the necessity to dissect the host immune response. In this study we compared the host response in lethal and non-lethal murine models of O. tsutsugamushi infection using the two strains, Karp (New Guinea) and Woods (Australia). The models included the lethal model: Karp intraperitoneal (IP) challenge; and the nonlethal models: Karp intradermal (ID), Woods IP, and Woods ID challenges. We monitored bacterial trafficking to the liver, lung, spleen, kidney, heart, and blood, and seroconversion during the 21-day challenge. Bacterial trafficking to all organs was observed in both the lethal and nonlethal models of infection, with significant increases in average bacterial loads observed in the livers and hearts of the lethal model. Multicolor flow cytometry was utilized to analyze the CD4+ and CD8+ T cell populations and their intracellular production of the cytokines IFNγ, TNF, and IL2 (single, double, and triple combinations) associated with both the lethal and nonlethal murine models of infection. The lethal model was defined by a cytokine signature of double- (IFNγ-IL2) and triple-producing (IL2-TNF-IFNγ) CD4+ T-cell populations; no multifunctional signature was identified in the CD8+ T-cell populations associated with the lethal model. In the nonlethal model, the cytokine signature was predominated by CD4+ and CD8+ T-cell populations associated with single (IL2) and/or double (IL2-TNF) populations of producers. The cytokine signatures associated with our lethal model will become depletion targets in future experiments; those signatures associated with our nonlethal model are hypothesized to be related to the protective nature of the nonlethal challenges.

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Differentiation of Effector CD4 T Cell Populations

Annual Review of Immunology ◽

10.1146/annurev-immunol-030409-101212 ◽

2010 ◽

Vol 28 (1) ◽

pp. 445-489 ◽

Cited By ~ 1793

Author(s):

Jinfang Zhu ◽

Hidehiro Yamane ◽

William E. Paul

Keyword(s):

T Cell ◽

Cd4 T Cell ◽

Cell Populations

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Effective CD4+ T-cell restoration in gut-associated lymphoid tissue of HIV-infected patients is associated with enhanced Th17 cells and polyfunctional HIV-specific T-cell responses

Mucosal Immunology ◽

10.1038/mi.2008.35 ◽

2008 ◽

Vol 1 (6) ◽

pp. 475-488 ◽

Cited By ~ 127

Author(s):

M Macal ◽

S Sankaran ◽

T-W Chun ◽

E Reay ◽

J Flamm ◽

...

Keyword(s):

T Cell ◽

Lymphoid Tissue ◽

Th17 Cells ◽

T Cell Responses ◽

Cd4 T Cell ◽

Cell Responses

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Intracolonic Neuropeptide Y Y1 Receptor Inhibition Attenuates Intestinal Inflammation in Murine Colitis and Cytokine Release in IBD Biopsies

Inflammatory Bowel Diseases ◽

10.1093/ibd/izab243 ◽

2021 ◽

Author(s):

Bindu Chandrasekharan ◽

Darra Boyer ◽

Joshua A Owens ◽

Alexandra A Wolfarth ◽

Bejan J Saeedi ◽

...

Keyword(s):

T Cell ◽

Neuropeptide Y ◽

Intestinal Inflammation ◽

Ex Vivo ◽

Cytokine Release ◽

Dss Colitis ◽

Receptor Inhibition ◽

Cytokine Tumor Necrosis Factor ◽

Ifn Γ ◽

T Cell Transfer

Abstract We have demonstrated that neuropeptide Y (NPY) can regulate pro-inflammatory signaling in the gut via cross-talk with the pro-inflammatory cytokine tumor necrosis factor (TNF). Here, we investigated if selective blocking of NPY receptors, NPY1R or NPY2R, using small molecule non-peptide antagonists (BIBP-3222 for NPY1R and BIIE-0246 for NPY2R) in the colon could attenuate intestinal inflammation by lowering TNF levels (BIBP - N-[(1R)]-4-[(Aminoiminomethyl)amino-1-[[[(4-hydroxyphenyl)methyl]amino]carbonyl]butyl-α-phenylbenzeneacetamide; BIIE - N-[(1S)-4-[(Aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide). Colitis was induced using dextran sodium sulfate in drinking water for 7 days, or by adoptive T-cell transfer in RAG-/- mice. Colonic biopsies from healthy subjects (n = 10) and IBD patients (n = 34, UC = 20, CD = 14) were cultured ex vivo in presence or absence of NPY antagonists (100 µM, 20 h), and cytokine release into culture supernatants was measured by ELISA. Intracolonic administration of BIBP (but not BIIE) significantly reduced clinical, endoscopic, and histological scores, and serum TNF, interleukin (IL)-6, and IL-12p70 in DSS colitis; it also significantly attenuated histological damage and serum IL-6 in T-cell colitis (P < .05). Intracolonic administration of BIBP significantly reduced TNF and interferon (IFN)-γ release from UC biopsies, whereas BIIE downregulated only IFN-γ (P < .05). BIBP significantly reduced TNF and interferon (IFN)-γ release from UC biopsies, whereas BIIE downregulated only IFN-γ (P < .05). Our data suggest a promising therapeutic value for NPY1R inhibition in alleviating intestinal inflammation in UC, possibly as enemas to IBD patients.

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