γδ T cells regulate the intestinal response to nutrient sensing

Science ◽  
2021 ◽  
Vol 371 (6535) ◽  
pp. eaba8310
Author(s):  
Zuri A. Sullivan ◽  
William Khoury-Hanold ◽  
Jaechul Lim ◽  
Chris Smillie ◽  
Moshe Biton ◽  
...  
Keyword(s):  
T Cells ◽  
Nutrient Uptake ◽  
Γδ T Cells ◽  
Nutrient Sensing ◽  
Lymphoid Cells ◽  
Transcriptional Responses ◽  
Interleukin 22 ◽  
Epithelial Compartment ◽  
A Site ◽  
Type 3

The intestine is a site of direct encounter with the external environment and must consequently balance barrier defense with nutrient uptake. To investigate how nutrient uptake is regulated in the small intestine, we tested the effect of diets with different macronutrient compositions on epithelial gene expression. We found that enzymes and transporters required for carbohydrate digestion and absorption were regulated by carbohydrate availability. The “on-demand” induction of this machinery required γδ T cells, which regulated this program through the suppression of interleukin-22 production by type 3 innate lymphoid cells. Nutrient availability altered the tissue localization and transcriptome of γδ T cells. Additionally, transcriptional responses to diet involved cellular remodeling of the epithelial compartment. Thus, this work identifies a role for γδ T cells in nutrient sensing.

scholarly journals Role of Common γ-Chain Cytokines in Lung Interleukin-22 Regulation after Acute Exposure to Aspergillus fumigatus

2018 ◽  
Vol 86 (10) ◽  
Author(s):  
Kristen M. Reeder ◽  
Joseph J. Mackel ◽  
Matthew S. Godwin ◽  
Chad W. Dunaway ◽  
Jonathan P. Blackburn ◽  
...  
Keyword(s):  
T Cells ◽  
Aspergillus Fumigatus ◽  
Γδ T Cells ◽  
Protective Role ◽  
Lymphoid Cells ◽  
Inkt Cells ◽  
Content Type ◽  
Interleukin 22 ◽  
Cell Sources

ABSTRACT Humans are constantly exposed to the opportunistic mold Aspergillus fumigatus, and disease caused by this pathogen is often determined by the magnitude of local and systemic immune responses. We have previously shown a protective role for interleukin-22 (IL-22) after acute A. fumigatus exposure. Here, employing IL-22Cre R26ReYFP reporter mice, we identified iNKT cells, γδ T cells, and type 3 innate lymphoid cells (ILC3s) as lung cell sources of IL-22 in response to acute A. fumigatus exposure. As these cells often utilize common γ-chain cytokines for their development or maintenance, we determined the role of IL-7, IL-21, and IL-15 in lung IL-22 induction and A. fumigatus lung clearance. We observed that IL-7, IL-21, and IL-15 were essential for, partially required for, or negatively regulated the production of IL-22, respectively. Deficiency in IL-7 and IL-21, but not IL-15R, resulted in impaired fungal clearance. Surprisingly, however, the absence of IL-7, IL-21, or IL-15R signaling had no effect on neutrophil recruitment. The levels of IL-1α, an essential anti-A. fumigatus proinflammatory cytokine, were increased in the absence of IL-7 and IL-15R but decreased in the absence of IL-21. IL-7 was responsible for maintaining lung iNKT cells and γδ T cells, whereas IL-21 was responsible for maintaining lung iNKT cells and ILC3s. In contrast, IL-15R deficiency had no effect on the absolute numbers of any IL-22 cell source, rather resulting in enhanced per cell production of IL-22 by iNKT cells and γδ T cells. Collectively, these results provide insight into how the IL-22 response in the lung is shaped after acute A. fumigatus exposure.

scholarly journals P02.02 Single-cell RNA sequencing of neuroblastoma tumors reveals immunoregulatory interactions as novel targets for immunotherapy

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A8.1-A8
Author(s):  
J Wienke ◽  
WM Kholosy ◽  
LL Visser ◽  
KM Keller ◽  
P Lijnzaad ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Single Cell ◽  
Cell Function ◽  
Γδ T Cells ◽  
Lymphoid Cells ◽  
Gene Set Enrichment Analysis ◽  
Mycn Amplification ◽  
Solid Cancer ◽  
Novel Targets

BackgroundImmunotherapy with CAR-T cells, as well as immune checkpoint blockade, show limited clinical efficacy in the pediatric solid cancer neuroblastoma, despite the success in various adult cancers. The lacking efficacy may be due to various immune evasion strategies employed by neuroblastoma tumors, leading to altered functionality of tumor-infiltrating immune cells. We aimed to provide a comprehensive overview of the composition and function of the neuroblastoma immune environment, as well as relevant immunoregulatory interactions (=), to identify novel targets for immunotherapy.Materials and Methods25 tumor samples from 20 patients (17 with high-risk disease, 6 with MYCN amplification), were collected during diagnostic biopsy pre-treatment (n=10) or during resection surgery after induction chemotherapy (n=15). Samples were enzymatically digested, single-cell FACS sorted and sequenced by Cel-Seq2 protocol.ResultsLymphoid cells in the TME consisted of αβ-, γδ-T cells, NK cells and B cells. Among αβ-T cells we identified CD8+ T cells, two functionally distinct clusters of CD4+ T cells, naive-like T cells and FOXP3+ regulatory T cells (Tregs). CD8+ T cells had reduced cytotoxic capacity compared to blood-derived T cells from a reference group. Tregs expressed high levels of PRDM1, LAYN and ICOS, suggesting an effector Treg profile, which is associated with increased inhibitory capacity. Although NK cells expressed the cytotoxic genes NKG7, KLRF1, GNLY, GZMB and PRF1, their expression was significantly lower than in blood-derived reference NK cells. Gene set enrichment analysis (GSEA) confirmed a reduced cytotoxic capacity of tumoral NK cells, which correlated with a decreased expression of activating receptors (r=0.41, p<0.001) and increased TGFβ signaling (r=-0.45, p<0.001). In addition, NK cells highly expressed the heterodimeric receptor KLRC1:KLRD1, which can inhibit NK cell function through HLA-E binding. High HLA-E expression by endothelial, immune and mesenchymal cells confirmed its inhibitory activity in the TME. Within the myeloid compartment we identified various immunosuppressive populations, comprising a cluster of IL10 and VEGFA expressing macrophages, three clusters of M2 differentiated macrophages expressing MMP9 and LGALS3, and dendritic cells with intact antigen presenting capacity, but high expression of numerous genes encoding immunosuppressive molecules such as IDO1, LGALS1, LGALS2, CCL22 and NECTIN2. In MYCN amplified tumors, specifically, we observed even lower cytotoxic capacity of CD8+ T and NK cells. We identified increased TGFB1 expression and defective antigen presentation by myeloid and tumor cells as potential causes for reduced cytotoxicity in MYCN amplified tumors. To identify relevant targets for immunotherapy we constructed an unbiased interaction network, which revealed NECTIN1=CD96 and MIF=CD74 as active immunoregulatory interactions between tumor and T/NK cells, and CD80/CD86=CTLA4, CLEC2D=KLRB1, HLA-E=KLRC1/KLRC2, CD99=PILRA, LGALS9=HAVCR2, and NECTIN2=TIGIT between myeloid and T/NK cells.ConclusionsCytotoxic lymphocytes in the neuroblastoma TME show reduced cytotoxic capacity, likely due to highly immunosuppressive myeloid cells, Tregs and numerous immunoregulatory interactions, which may serve as novel targets for immunotherapy in neuroblastoma.Disclosure InformationJ. Wienke: None. W.M. Kholosy: None. L.L. Visser: None. K.M. Keller: None. P. Lijnzaad: None. T. Margaritis: None. K.P.S. Langenberg: None. R.R. De Krijger: None. F.C.P. Holstege: None. J.J. Molenaar: None.

scholarly journals IL-22 and its receptors are increased in human and experimental COPD and contribute to pathogenesis

2019 ◽  
Vol 54 (1) ◽  
pp. 1800174 ◽  
Author(s):  
Malcolm R. Starkey ◽  
Maximilian W. Plank ◽  
Paolo Casolari ◽  
Alberto Papi ◽  
Stelios Pavlidis ◽  
...  
Keyword(s):  
T Cells ◽  
Γδ T Cells ◽  
Lymphoid Cells ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Protein Levels ◽  
Copd Patients ◽  
Cellular Source ◽  
Group 3 ◽  
Underlying Mechanisms

Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death globally. The lack of effective treatments results from an incomplete understanding of the underlying mechanisms driving COPD pathogenesis.Interleukin (IL)-22 has been implicated in airway inflammation and is increased in COPD patients. However, its roles in the pathogenesis of COPD is poorly understood. Here, we investigated the role of IL-22 in human COPD and in cigarette smoke (CS)-induced experimental COPD.IL-22 and IL-22 receptor mRNA expression and protein levels were increased in COPD patients compared to healthy smoking or non-smoking controls. IL-22 and IL-22 receptor levels were increased in the lungs of mice with experimental COPD compared to controls and the cellular source of IL-22 included CD4+ T-helper cells, γδ T-cells, natural killer T-cells and group 3 innate lymphoid cells. CS-induced pulmonary neutrophils were reduced in IL-22-deficient (Il22−/−) mice. CS-induced airway remodelling and emphysema-like alveolar enlargement did not occur in Il22−/− mice. Il22−/− mice had improved lung function in terms of airway resistance, total lung capacity, inspiratory capacity, forced vital capacity and compliance.These data highlight important roles for IL-22 and its receptors in human COPD and CS-induced experimental COPD.

scholarly journals A fetal wave of human type 3 effector γδ cells with restricted TCR diversity persists into adulthood

2021 ◽  
Vol 6 (58) ◽  
pp. eabf0125
Author(s):  
Likai Tan ◽  
Alina Suzann Fichtner ◽  
Elena Bruni ◽  
Ivan Odak ◽  
Inga Sandrock ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Throughput Sequencing ◽  
Γδ T Cells ◽  
Cell Types ◽  
Multiparameter Flow Cytometry ◽  
Expression Of Genes ◽  
Innate Effector ◽  
Type 3

Accumulating evidence suggests that the mouse embryonic thymus produces distinct waves of innate effector γδ T cells. However, it is unclear whether this process occurs similarly in humans and whether it comprises a dedicated subset of innate-like type 3 effector γδ T cells. Here, we present a protocol for high-throughput sequencing of TRG and TRD pairs that comprise the clonal γδTCR. In combination with single-cell RNA sequencing, multiparameter flow cytometry, and TCR sequencing, we reveal a high heterogeneity of γδ T cells sorted from neonatal and adult blood that correlated with TCR usage. Immature γδ T cell clusters displayed mixed and diverse TCRs, but effector cell types segregated according to the expression of either highly expanded individual Vδ1+ TCRs or moderately expanded semi-invariant Vγ9Vδ2+ TCRs. The Vγ9Vδ2+ T cells shared expression of genes that mark innate-like T cells, including ZBTB16 (encoding PLZF), KLRB1, and KLRC1, but consisted of distinct clusters with unrelated Vγ9Vδ2+ TCR clones characterized either by TBX21, FCGR3A, and cytotoxicity-associated gene expression (type 1) or by CCR6, RORC, IL23R, and DPP4 expression (type 3). Effector γδ T cells with type 1 and type 3 innate T cell signatures were detected in a public dataset of early embryonic thymus organogenesis. Together, this study suggests that functionally distinct waves of human innate-like effector γδ T cells with semi-invariant Vγ9Vδ2+ TCR develop in the early fetal thymus and persist into adulthood.

scholarly journals Type 3 Immunity during Clostridioides difficile Infection: Too Much of a Good Thing?

2019 ◽  
Vol 88 (1) ◽  
Author(s):  
Mahmoud M. Saleh ◽  
William A. Petri
Keyword(s):  
The United States ◽  
Lymphoid Cells ◽  
Interleukin 17 ◽  
Gastrointestinal Infections ◽  
Content Type ◽  
Animal Models Of Disease ◽  
Interleukin 22 ◽  
Inflammatory Conditions ◽  
Clostridioides Difficile ◽  
Type 3

ABSTRACT Clostridioides (formerly known as Clostridium) difficile is the leading cause of hospital-acquired gastrointestinal infections in the United States and one of three urgent health care threats identified by the Centers for Disease Control and Prevention. C. difficile disease is mediated by the production of toxins that disrupt the epithelial barrier and cause a robust host inflammatory response. Studies in humans as well as animal models of disease have shown that the type of immune response generated against the infection dictates the outcome of disease, often irrespective of bacterial burden. Much of the focus on immunity during C. difficile infection (CDI) has been on type 3 immunity because of the established role for this arm of the immune system in other gastrointestinal inflammatory conditions such as inflammatory bowel disease (IBD). For example, interleukin-22 (IL-22) production by group 3 innate lymphoid cells (ILC3s) protects against pathobionts translocating across the epithelium during CDI. On the other hand, interleukin-17 (IL-17) production by Th17 cells increases CDI-associated mortality. Additionally, neutropenia has been associated with increased susceptibility to CDI in humans, but increased neutrophilia in mouse models correlates with host pathology. Taking the data together, these findings suggest dual roles for type 3 immune responses during infection. Here, we review the complex role of type 3 immunity during CDI and delineate what is known about innate and adaptive cellular immunity as well as the downstream effector cytokines known to be important during this infection.

scholarly journals Oral-resident natural Th17 cells and γδ T cells control opportunistic Candida albicans infections

2014 ◽  
Vol 211 (10) ◽  
pp. 2075-2084 ◽  
Author(s):  
Heather R. Conti ◽  
Alanna C. Peterson ◽  
Lucas Brane ◽  
Anna R. Huppler ◽  
Nydiaris Hernández-Santos ◽  
...  
Keyword(s):  
T Cells ◽  
Candida Albicans ◽  
Γδ T Cells ◽  
Clonal Diversity ◽  
Lymphoid Cells ◽  
Innate Response ◽  
Tcr Signaling ◽  
Reporter Mice ◽  
Mucosal Surfaces ◽  
Oral Pathogens

Oropharyngeal candidiasis (OPC) is an opportunistic fungal infection caused by Candida albicans. OPC is frequent in HIV/AIDS, implicating adaptive immunity. Mice are naive to Candida, yet IL-17 is induced within 24 h of infection, and susceptibility is strongly dependent on IL-17R signaling. We sought to identify the source of IL-17 during the early innate response to candidiasis. We show that innate responses to Candida require an intact TCR, as SCID, IL-7Rα−/−, and Rag1−/− mice were susceptible to OPC, and blockade of TCR signaling by cyclosporine induced susceptibility. Using fate-tracking IL-17 reporter mice, we found that IL-17 is produced within 1–2 d by tongue-resident populations of γδ T cells and CD3+CD4+CD44hiTCRβ+CCR6+ natural Th17 (nTh17) cells, but not by TCR-deficient innate lymphoid cells (ILCs) or NK cells. These cells function redundantly, as TCR-β−/− and TCR-δ−/− mice were both resistant to OPC. Whereas γδ T cells were previously shown to produce IL-17 during dermal candidiasis and are known to mediate host defense at mucosal surfaces, nTh17 cells are poorly understood. The oral nTh17 population expanded rapidly after OPC, exhibited high TCR-β clonal diversity, and was absent in Rag1−/−, IL-7Rα−/−, and germ-free mice. These findings indicate that nTh17 and γδ T cells, but not ILCs, are key mucosal sentinels that control oral pathogens.

scholarly journals Role of IL-17A in murine models of COPD airway disease

2017 ◽  
Vol 312 (1) ◽  
pp. L122-L130 ◽  
Author(s):  
Haruhiko Yanagisawa ◽  
Mitsuo Hashimoto ◽  
Shunsuke Minagawa ◽  
Naoki Takasaka ◽  
Royce Ma ◽  
...  
Keyword(s):  
T Cells ◽  
Airway Inflammation ◽  
Γδ T Cells ◽  
Small Airway ◽  
Lymphoid Cells ◽  
Chronic Obstructive ◽  
Polymorphonuclear Cells ◽  
Small Airways ◽  
Pathological Feature ◽  
Airway Fibrosis

Small airway fibrosis is a major pathological feature of chronic obstructive pulmonary disease (COPD) and is refractory to current treatments. Chronic inflammatory cells accumulate around small airways in COPD and are thought to play a major role in small airway fibrosis. Mice deficient in α/β T cells have recently been shown to be protected from both experimental airway inflammation and fibrosis. In these models, CD4+Th17 cells and secretion of IL-17A are increased. However, a pathogenic role for IL-17 in specifically mediating fibrosis around airways has not been demonstrated. Here a role for IL-17A in airway fibrosis was demonstrated using mice deficient in the IL-17 receptor A ( il17ra). Il17ra-deficient mice were protected from both airway inflammation and fibrosis in two different models of airway fibrosis that employ COPD-relevant stimuli. In these models, CD4+ Th17 are a major source of IL-17A with other expressing cell types including γδ T cells, type 3 innate lymphoid cells, polymorphonuclear cells, and CD8+ T cells. Antibody neutralization of IL-17RA or IL-17A confirmed that IL-17A was the relevant pathogenic IL-17 isoform and IL-17RA was the relevant receptor in airway inflammation and fibrosis. These results demonstrate that the IL-17A/IL-17 RA axis is crucial to murine airway fibrosis. These findings suggest that IL-17 might be targeted to prevent the progression of airway fibrosis in COPD.

scholarly journals Regulation of contact hypersensitivity by interleukin 10.

1994 ◽  
Vol 179 (5) ◽  
pp. 1597-1604 ◽  
Author(s):  
T A Ferguson ◽  
P Dube ◽  
T S Griffith
Keyword(s):  
T Cells ◽  
Neutralizing Antibody ◽  
Inflammatory Cells ◽  
Interleukin 10 ◽  
Lymphoid Cells ◽  
Contact Hypersensitivity ◽  
Mrna Transcription ◽  
Antigenic Challenge ◽  
A Site

Contact hypersensitivity (CHS) responses require the participation of T cells, along with a variety of cytokines and adhesion molecules. In the classical CHS, antigen-specific T cells are recruited to a site of antigenic challenge, where they react with antigen, release cytokines, and attract other inflammatory cells. In the mouse model of CHS, this reaction is elicited in sensitized mice by application of the immunogen 4-7 d after immunization. The reaction peaks at 24 h, is slightly reduced by 48 h, and can return to normal by 72 h. This is in spite of the fact that some antigen is still present at the site of challenge. Here we examined the hypothesis that locally produced interleukin 10 (IL-10) regulates the duration of the response. Our data show that IL-10 protein peaked 10-14 h after antigenic challenge and returned to background by 24 h. The production of IL-10 protein corresponded with, and followed IL-10 mRNA transcription as detected by reverse transcriptase-polymerase chain reaction. During peak IL-10 production after antigenic challenge, it was not possible to transfer CHS with immune lymphoid cells, unless neutralizing antibody to IL-10 was given first. Additionally, when sensitized mice were given neutralizing anti-IL-10 antibody at the time of antigenic challenge, the duration of CHS was prolonged well beyond the natural course of the response. Finally, we demonstrate that rIL-10, when injected into the skin before antigenic challenge, prevented the elicitation of CHS in previously sensitized mice. Taken together, our data show an important role for IL-10 in the natural regulation of CHS responses in vivo.

scholarly journals Inhibitor of apoptosis proteins 1 and 2 are required for the homeostasis of murine RORγt+ γδ T cells

2020 ◽  
Author(s):  
John Rizk ◽  
Rasmus Agerholm ◽  
Darshana Kadekar ◽  
Monica Torrellas Viñals ◽  
Vasileios Bekiaris
Keyword(s):  
T Cells ◽  
Adult Life ◽  
Γδ T Cells ◽  
Lymphoid Cells ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Proteins ◽  
Extrinsic Factors ◽  
Thymic Development ◽  
Adult Mice ◽  
Apoptosis Proteins

AbstractRORγt+ γδ T cells, known as γδT17, are an innate-like subset of T cells that produce interleukin (IL)-17A and initiate type 3 immune responses during infections or autoimmune pathologies. Herein we show that the cellular inhibitor of apoptosis proteins cIAP1 and 2 are required for the peripheral homeostasis of γδT17 but not for their thymic development. γδT17 cells that were deficient in both cIAP1 and 2 were profoundly reduced in the peripheral lymph nodes and skin. Likewise, both RORγt+ innate lymphoid cells (ILC3) and RORγt+ Tbet+ γδ T cells were reduced in the lamina propria of adult mice. Further, cIAP1 and 2 were required for the expression of the transcription factors RORγt and cMAF in γδT17 cells during neonatal and adult life. Single deficiency of either cIAP1 or 2 did not affect the homeostasis or transcription factor profile of γδT17 cells. Moreover, bone marrow reconstitutions and transfer of neonatal γδ T cells to RAG1−/− hosts showed that both intrinsic and extrinsic factors contribute to the loss of γδT17 cells in cIAP1/2 double deficient mice, while only extrinsic signals were responsible for the decrease of ILC3 cells. Deficiency of γδT17 cells in cIAP1 and cIAP2 double deficient animals, or the presence of functionally defective γδT17 cells did not confer protection against IMQ-induced psoriasis. Collectively, our data reveal a previously undescribed role for cIAP1 and cIAP2 in the homeostasis of γδT17 and ILC3 cells.

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