A CCL1/CCR8-dependent feed-forward mechanism drives ILC2 functions in type 2–mediated inflammation

Group 2 innate lymphoid cells (ILC2s) possess indispensable roles during type 2–mediated inflammatory diseases. Although their physiological and detrimental immune functions seem to depend on the anatomical compartment they reside, their tissue tropism and the molecular and immunological processes regulating the self-renewal of the local pool of ILC2s in the context of inflammation or infection are incompletely understood. Here, we analyzed the role of the CC-chemokine receptor CCR8 for the biological functions of ILC2s. In vitro and in vivo experiments indicated that CCR8 is in comparison to the related molecule CCR4 less important for migration of these cells. However, we found that activated mouse and human ILC2s produce the CCR8 ligand CCL1 and are a major source of CCL1 in vivo. CCL1 signaling to ILC2s regulates their proliferation and supports their capacity to protect against helminthic infections. In summary, we identify a novel chemokine receptor–dependent mechanism by which ILC2s are regulated during type 2 responses.

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Acetylcholine production by group 2 innate lymphoid cells promotes mucosal immunity to helminths

Science Immunology ◽

10.1126/sciimmunol.abd0359 ◽

2021 ◽

Vol 6 (57) ◽

pp. eabd0359

Author(s):

Luke B. Roberts ◽

Corinna Schnoeller ◽

Rita Berkachy ◽

Matthew Darby ◽

Jamie Pillaye ◽

...

Keyword(s):

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Mucosal Barrier ◽

Nippostrongylus Brasiliensis ◽

Interleukin 33 ◽

Group 2 ◽

Maximal Induction

Innate lymphoid cells (ILCs) are critical mediators of immunological and physiological responses at mucosal barrier sites. Whereas neurotransmitters can stimulate ILCs, the synthesis of small-molecule neurotransmitters by these cells has only recently been appreciated. Group 2 ILCs (ILC2s) are shown here to synthesize and release acetylcholine (ACh) during parasitic nematode infection. The cholinergic phenotype of pulmonary ILC2s was associated with their activation state, could be induced by in vivo exposure to extracts of Alternaria alternata or the alarmin cytokines interleukin-33 (IL-33) and IL-25, and was augmented by IL-2 in vitro. Genetic disruption of ACh synthesis by murine ILC2s resulted in increased parasite burdens, lower numbers of ILC2s, and reduced lung and gut barrier responses to Nippostrongylus brasiliensis infection. These data demonstrate a functional role for ILC2-derived ACh in the expansion of ILC2s for maximal induction of type 2 immunity.

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The transcription factor Bcl11b is specifically expressed in group 2 innate lymphoid cells and is essential for their development

Journal of Experimental Medicine ◽

10.1084/jem.20142318 ◽

2015 ◽

Vol 212 (6) ◽

pp. 865-874 ◽

Cited By ~ 94

Author(s):

Yong Yu ◽

Cui Wang ◽

Simon Clare ◽

Juexuan Wang ◽

Song-Choon Lee ◽

...

Keyword(s):

Transcription Factor ◽

Cell Lineage ◽

Influenza Virus Infection ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Effector Cytokines ◽

Group 2

Group 2 innate lymphoid cells (ILCs), or ILC2s, are a subset of recently identified ILCs, which play important roles in innate immunity by producing type 2 effector cytokines. Several transcription factors have been found to have critical functions in the development of both ILC2s and T cells. We report here that Bcl11b, a transcription factor essential in T cell lineage commitment and maintenance, is specifically expressed in progenitors committed to the ILC2 lineage and is required for ILC2 development. The Bcl11b gene is expressed in ∼28% of ILC progenitors (ILCPs; common helper innate lymphoid progenitors or ILCPs expressing either ID2 or promyelocytic leukemia zinc finger, respectively). Both in vitro and in vivo, these Bcl11b-expressing early ILCPs generate only ILC2s. Inactivation of Bcl11b causes a complete loss of ILC2 development from hematopoietic progenitors, which is confirmed upon immune challenge with either papain administration or influenza virus infection.

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Cc Chemokine Receptor (Ccr)3/Eotaxin Is Followed by Ccr4/Monocyte-Derived Chemokine in Mediating Pulmonary T Helper Lymphocyte Type 2 Recruitment after Serial Antigen Challenge in Vivo

Journal of Experimental Medicine ◽

10.1084/jem.191.2.265 ◽

2000 ◽

Vol 191 (2) ◽

pp. 265-274 ◽

Cited By ~ 230

Author(s):

Clare M. Lloyd ◽

Tracy Delaney ◽

Trang Nguyen ◽

Jane Tian ◽

Carlos Martinez-A ◽

...

Keyword(s):

Chemokine Receptor ◽

Progressive Increase ◽

Allergic Airway Disease ◽

Antigen Challenge ◽

Th2 Cells ◽

T Helper ◽

Cc Chemokine

Isolated peripheral blood CD4 cells from allergic individuals express CC chemokine receptor (CCR)3 and CCR4 after expansion in vitro. In addition, human T helper type 2 (Th2) cells polarized in vitro selectively express CCR3 and CCR4 at certain stages of activation/differentiation and respond preferentially to the ligands eotaxin and monocyte-derived chemokine (MDC). However, controversy arises when the in vivo significance of this distinct expression is discussed. To address the functional role of CCR3/eotaxin and CCR4/MDC during the in vivo recruitment of Th2 cells, we have transferred effector Th cells into naive mice to induce allergic airway disease. Tracking of these cells after repeated antigen challenge has established that both CCR3/eotaxin and CCR4/MDC axes contribute to the recruitment of Th2 cells to the lung, demonstrating the in vivo relevance of the expression of these receptors on Th2 cells. We have shown that involvement of the CCR3/eotaxin pathway is confined to early stages of the response in vivo, whereas repeated antigen stimulation results in the predominant use of the CCR4/MDC pathway. We propose that effector Th2 cells respond to both CCR3/eotaxin and CCR4/MDC pathways initially, but that a progressive increase in CCR4-positive cells results in the predominance of the CCR4/MDC axis in the long-term recruitment of Th2 cells in vivo.

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Activation of group 2 innate lymphoid cells alleviates aging-associated cognitive decline

Journal of Experimental Medicine ◽

10.1084/jem.20190915 ◽

2020 ◽

Vol 217 (4) ◽

Cited By ~ 6

Author(s):

Ivan Ting Hin Fung ◽

Poornima Sankar ◽

Yuanyue Zhang ◽

Lisa S. Robison ◽

Xiuli Zhao ◽

...

Keyword(s):

Cognitive Decline ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Brain Physiology ◽

Aged Brain ◽

Group 2 ◽

Resident Group ◽

And Function

Increasing evidence has challenged the traditional view about the immune privilege of the brain, but the precise roles of immune cells in regulating brain physiology and function remain poorly understood. Here, we report that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the choroid plexus of aged brains. ILC2 in the aged brain are long-lived, are relatively resistant to cellular senescence and exhaustion, and are capable of switching between cell cycle dormancy and proliferation. They are functionally quiescent at homeostasis but can be activated by IL-33 to produce large amounts of type 2 cytokines and other effector molecules in vitro and in vivo. Intracerebroventricular transfer of activated ILC2 revitalized the aged brain and enhanced the cognitive function of aged mice. Administration of IL-5, a major ILC2 product, was sufficient to repress aging-associated neuroinflammation and alleviate aging-associated cognitive decline. Targeting ILC2 in the aged brain may provide new avenues to combat aging-associated neurodegenerative disorders.

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The ETS1 transcription factor is required for the development and cytokine-induced expansion of ILC2

Journal of Experimental Medicine ◽

10.1084/jem.20150851 ◽

2016 ◽

Vol 213 (5) ◽

pp. 687-696 ◽

Cited By ~ 44

Author(s):

Erin C. Zook ◽

Kevin Ramirez ◽

Xiaohuan Guo ◽

Grant van der Voort ◽

Mikael Sigvardsson ◽

...

Keyword(s):

Transcription Factor ◽

Messenger Rna ◽

Critical Factor ◽

Protective Role ◽

Lymphoid Cells ◽

Allergic Lung Inflammation ◽

Factor Inhibitor ◽

Group 2

Group 2 innate lymphoid cells (ILC2s) are a subset of ILCs that play a protective role in the response to helminth infection, but they also contribute to allergic lung inflammation. Here, we report that the deletion of the ETS1 transcription factor in lymphoid cells resulted in a loss of ILC2s in the bone marrow and lymph nodes and that ETS1 promotes the fitness of the common progenitor of all ILCs. ETS1-deficient ILC2 progenitors failed to up-regulate messenger RNA for the E protein transcription factor inhibitor ID2, a critical factor for ILCs, and these cells were unable to expand in cytokine-driven in vitro cultures. In vivo, ETS1 was required for the IL-33–induced accumulation of lung ILC2s and for the production of the T helper type 2 cytokines IL-5 and IL-13. IL-25 also failed to elicit an expansion of inflammatory ILC2s when these cells lacked ETS1. Our data reveal ETS1 as a critical regulator of ILC2 expansion and cytokine production and implicate ETS1 in the regulation of Id2 at the inception of ILC2 development.

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IL-27 suppresses type 2 immune responses in vivo via direct effects on group 2 innate lymphoid cells

Mucosal Immunology ◽

10.1038/mi.2016.20 ◽

2016 ◽

Vol 9 (6) ◽

pp. 1384-1394 ◽

Cited By ~ 40

Author(s):

T Mchedlidze ◽

M Kindermann ◽

A T Neves ◽

D Voehringer ◽

M F Neurath ◽

...

Keyword(s):

Immune Responses ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

Direct Effects ◽

Group 2

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Group 2 Innate Lymphoid Cells Exhibit Tissue-Specific Dynamic Behaviour During Type 2 Immune Responses

Frontiers in Immunology ◽

10.3389/fimmu.2021.711907 ◽

2021 ◽

Vol 12 ◽

Author(s):

Laurence S. C. Lok ◽

Jennifer A. Walker ◽

Helen E. Jolin ◽

Seth T. Scanlon ◽

Masaru Ishii ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Intestinal Mucosa ◽

Dynamic Behaviour ◽

Helminth Infection ◽

Lymphoid Cells ◽

Group 2

Group 2 innate lymphoid cells (ILC2s) are early effectors of mucosal type 2 immunity, producing cytokines such as interleukin (IL)-13 to mediate responses to helminth infection and allergen-induced inflammation. ILC2s are also present in lymph nodes (LNs) and can express molecules required for antigen presentation, but to date there are limited data on their dynamic behaviour. We used a CD2/IL-13 dual fluorescent reporter mouse for in vivo imaging of ILC2s and Th2 T cells in real time following a type 2 priming helminth infection or egg injection. After helminth challenge, we found that ILC2s were the main source of IL-13 in lymphoid organs (Peyer’s patches and peripheral LNs), and were located in T cell areas. Intravital imaging demonstrated an increase in IL-13+ ILC2 size and movement following helminth infection, but reduced duration of interactions with T cells compared with those in homeostasis. In contrast, in the intestinal mucosa, we observed an increase in ILC2-T cell interactions post-infection, including some of prolonged duration, as well as increased IL-13+ ILC2 movement. These data suggest that ILC2 activation enhances cell motility, with the potential to increase the area of distribution of cytokines to optimise the early generation of type 2 responses. The prolonged ILC2 interactions with T cells within the intestinal mucosa are consistent with the conclusion that contact-based T cell activation may occur within inflamed tissues rather than lymphoid organs. Our findings have important implications for our understanding of the in vivo biology of ILC2s and the way in which these cells facilitate adaptive immune responses.

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The Anti-Inflammatory Activity of HMGB1 A Box Is Enhanced When Fused with C-Terminal Acidic Tail

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/915234 ◽

2010 ◽

Vol 2010 ◽

pp. 1-6 ◽

Cited By ~ 13

Author(s):

Wei Gong ◽

Yingru Zheng ◽

Fan Chao ◽

Yuan Li ◽

Zhizhen Xu ◽

...

Keyword(s):

Fusion Proteins ◽

Inflammatory Diseases ◽

Inflammatory Activity ◽

In Vivo Experiments ◽

Specific Antagonist ◽

Proinflammatory Activity ◽

Anti Inflammatory ◽

Inflammatory Effect

HMGB1, composed of the A box, B box, and C tail domains, is a critical proinflammatory cytokine involved in diverse inflammatory diseases. The B box mediates proinflammatory activity, while the A box alone acts as a specific antagonist of HMGB1. The C tail contributes to the spatial structure of A box and regulates HMGB1 DNA binding specificity. It is unknown whether the C tail can enhance the anti-inflammatory effect of A box. In this study, we generated fusion proteins consisting of the A box and C tail, in which the B box was deleted and the A box and C tail were linked either directly or by the flexible linker sequence(Gly4Ser)3. In vitro and in vivo experiments showed that the two fusion proteins had a higher anti-inflammatory activity compared to the A box alone. This suggests that the fused C tail enhances the anti-inflammatory effect of the A box.

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ILC2-derived IL-9 inhibit s colorectal cancer progression by activating CD8+ T cells

10.21203/rs.3.rs-22746/v1 ◽

2020 ◽

Author(s):

Jie Wan ◽

Lan Huang ◽

Yinqiu Wu ◽

Xiaoyun Ji ◽

Shun Yao ◽

...

Keyword(s):

Colorectal Cancer ◽

Flow Cytometry ◽

T Cells ◽

Cancer Progression ◽

Normal Tissue ◽

Lymphoid Cells ◽

Adjacent Normal Tissue

Abstract Background Type 2 innate lymphoid cells (ILC2s), characterized by secreting type 2 cytokines, regulate multiple immune responses. ILC2s are found in different tumor tissues and ILC2-derived interleukin (IL)-4, IL-5, and IL-13 act on the cells in tumor microenvironment to participate in tumor progression. ILC2s are abundant in colorectal cancer (CRC) tissue, but the role of ILC2s in CRC remains unclear. Methods ILC2s were sorted from the spleen using microbeads combined with flow cytometry and tumor infiltrating CD8+ T cells were isolated from tumor tissue by microbeads. Flow cytometry and immunofluorescence were used to detect the percentage of ILC2s and CD8+ T cells in the spleen and CRC tissue. Effects of IL-9 and IL-9-stimulated CD8+ T cells on CT26 cells were measured by proliferation, apoptosis, and migration assays in vitro. GEPIA was used to detect the ILC2s chemokines in CRC tissue and adjacent normal tissue. Results We found that ILC2s were increased in CRC tissue compared with the adjacent normal tissue. In vitro experiments showed that IL-9 could activate CD8+ T cells to promote the death of CT26 cells. ILC2s were the main IL-9-secreting cells in CRC tissue as shown by flow cytometry analysis. In vivo experiments showed that neutralizing ILC2s promoted the tumor growth, while tumor inhibition occurred by intravenous injection of IL-9. Conclusions Our results demonstrated that ILC2-derived IL-9 activated CD8+ T cells to promote anti-tumor effects in CRC.

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