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

2020 ◽  
Vol 217 (4) ◽  
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.

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

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.

scholarly journals Group 2 innate lymphoid cells are numerically and functionally deficient in the triple transgenic mouse model of Alzheimer’s disease

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Ivan Ting Hin Fung ◽  
Yuanyue Zhang ◽  
Damian S. Shin ◽  
Poornima Sankar ◽  
Xiangwan Sun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease ◽  
Group 2 ◽  
Resident Group ◽  
And Function

Abstract Background The immune pathways in Alzheimer’s disease (AD) remain incompletely understood. Our recent study indicates that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the brain barriers of aged mice and that their activation alleviates aging-associated cognitive decline. The regulation and function of ILC2 in AD, however, remain unknown. Methods In this study, we examined the numbers and functional capability of ILC2 from the triple transgenic AD mice (3xTg-AD) and control wild-type mice. We investigated the effects of treatment with IL-5, a cytokine produced by ILC2, on the cognitive function of 3xTg-AD mice. Results We demonstrate that brain-associated ILC2 are numerically and functionally defective in the triple transgenic AD mouse model (3xTg-AD). The numbers of brain-associated ILC2 were greatly reduced in 7-month-old 3xTg-AD mice of both sexes, compared to those in age- and sex-matched control wild-type mice. The remaining ILC2 in 3xTg-AD mice failed to efficiently produce the type 2 cytokine IL-5 but gained the capability to express a number of proinflammatory genes. Administration of IL-5, a cytokine produced by ILC2, transiently improved spatial recognition and learning in 3xTg-AD mice. Conclusion Our results collectively indicate that numerical and functional deficiency of ILC2 might contribute to the cognitive impairment of 3xTg-AD mice.

scholarly journals IL-6 effector function of group 2 innate lymphoid cells (ILC2) is NOD2 dependent

2021 ◽  
Vol 6 (59) ◽  
pp. eabe5084
Author(s):  
Clare S. Hardman ◽  
Yi-Ling Chen ◽  
Maryam Salimi ◽  
Janina Nahler ◽  
Daniele Corridoni ◽  
...  
Keyword(s):  
Muramyl Dipeptide ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Interleukin 5 ◽  
Direct Sensing ◽  
Specific Receptors ◽  
Group 2 ◽  
Bacterial Sensing

Cutaneous group 2 innate lymphoid cells (ILC2) are spatially and epigenetically poised to respond to barrier compromise and associated immunological threats. ILC2, lacking rearranged antigen-specific receptors, are primarily activated by damage-associated cytokines and respond with type 2 cytokine production. To investigate ILC2 potential for direct sensing of skin pathogens and allergens, we performed RNA sequencing of ILC2 derived from in vivo challenged human skin or blood. We detected expression of NOD2 and TLR2 by skin and blood ILC2. Stimulation of ILC2 with TLR2 agonist alone not only induced interleukin-5 (IL-5) and IL-13 expression but also elicited IL-6 expression in combination with Staphylococcus aureus muramyl dipeptide (MDP). Heat-killed skin-resident bacteria provoked an IL-6 profile in ILC2 in vitro that was notably impaired in ILC2 derived from patients with nucleotide-binding oligomerization domain-containing protein 2 (NOD2) mutations. In addition, we show that NOD2 signaling can stimulate autophagy in ILC2, which was also impaired in patients with NOD2 mutations. Here, we have identified a role for ILC2 NOD2 signaling in the differential regulation of ILC2-derived IL-6 and have reported a previously unrecognized pathway of direct ILC2 bacterial sensing.

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

2015 ◽  
Vol 212 (6) ◽  
pp. 865-874 ◽  
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.

scholarly journals Transcription Factors in the Development and Function of Group 2 Innate Lymphoid Cells

2019 ◽  
Vol 20 (6) ◽  
pp. 1377 ◽  
Author(s):  
Takashi Ebihara ◽  
Ichiro Taniuchi
Keyword(s):  
Transcription Factors ◽  
Physiological State ◽  
Allergic Inflammation ◽  
Allergic Diseases ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Th2 Cytokine ◽  
Parasitic Worm ◽  
Group 2 ◽  
And Function

Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells and are a major source of innate TH2 cytokine secretion upon allergen exposure or parasitic-worm infection. Accumulating studies have revealed that transcription factors, including GATA-3, Bcl11b, Gfi1, RORα, and Ets-1, play a role in ILC2 differentiation. Recent reports have further revealed that the characteristics and functions of ILC2 are influenced by the physiological state of the tissues. Specifically, the type of inflammation strongly affects the ILC2 phenotype in tissues. Inhibitory ILC2s, memory-like ILC2s, and ex-ILC2s with ILC1 features acquire their characteristic properties following exposure to their specific inflammatory environment. We have recently reported a new ILC2 population, designated as exhausted-like ILC2s, which emerges after a severe allergic inflammation. Exhausted-like ILC2s are featured with low reactivity and high expression of inhibitory receptors. Therefore, for a more comprehensive understanding of ILC2 function and differentiation, we review the recent knowledge of transcriptional regulation of ILC2 differentiation and discuss the roles of the Runx transcription factor in controlling the emergence of exhausted-like ILC2s. The concept of exhausted-like ILC2s sheds a light on a new aspect of ILC2 biology in allergic diseases.

scholarly journals Immune checkpoints on innate lymphoid cells

2017 ◽  
Vol 214 (6) ◽  
pp. 1561-1563 ◽  
Author(s):  
Laura Chiossone ◽  
Eric Vivier
Keyword(s):  
Cytokine Production ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Negative Regulator ◽  
Immune Checkpoints ◽  
Group 2 ◽  
Blocking Antibodies

In this issue of JEM, Taylor et al. (https://doi.org/10.1084/jem.20161653) describe PD-1 as a critical negative regulator of group 2 innate lymphoid cells (ILC-2s). PD-1 intrinsically controls proliferation and cytokine production of both mouse and human ILC-2s. PD-1 signaling inhibits STAT5 phosphorylation and the removal of this brake by knocking down PD-1 expression or by using anti–PD-1 blocking antibodies, translated in vivo into better clearance of helminth worm infection in mice.

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

2016 ◽  
Vol 213 (5) ◽  
pp. 687-696 ◽  
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.

Human innate lymphoid cells

Blood ◽  
2014 ◽  
Vol 124 (5) ◽  
pp. 700-709 ◽  
Author(s):  
Mette D. Hazenberg ◽  
Hergen Spits
Keyword(s):  
Interferon Γ ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Interleukin 5 ◽  
Type 2 Cytokines ◽  
Lymphoid Tissue Inducer Cells ◽  
Health And Disease ◽  
Group 2 ◽  
And Function ◽  
Regulatory Functions

Innate lymphoid cells (ILCs) are lymphoid cells that do not express rearranged receptors and have important effector and regulatory functions in innate immunity and tissue remodeling. ILCs are categorized into 3 groups based on their distinct patterns of cytokine production and the requirement of particular transcription factors for their development and function. Group 1 ILCs (ILC1s) produce interferon γ and depend on Tbet, group 2 ILCs (ILC2s) produce type 2 cytokines like interleukin-5 (IL-5) and IL-13 and require GATA3, and group 3 ILCs (ILC3s) include lymphoid tissue inducer cells, produce IL-17 and/or IL-22, and are dependent on RORγt. Whereas ILCs play essential roles in the innate immune system, uncontrolled activation and proliferation of ILCs can contribute to inflammatory autoimmune diseases. In this review, we provide an overview of the characteristics of ILCs in the context of health and disease. We will focus on human ILCs but refer to mouse studies if needed to clarify aspects of ILC biology.

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

2016 ◽  
Vol 9 (6) ◽  
pp. 1384-1394 ◽  
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

scholarly journals Innate lymphoid cells lacking surface expression of CD90 are functional

2021 ◽  
Author(s):  
J-H Schroeder ◽  
T Zabinski ◽  
J F Neves ◽  
GM Lord
Keyword(s):  
Steady State ◽  
Cell Biology ◽  
Surface Expression ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
T Cell Biology ◽  
First Time ◽  
Made In

ABSTRACTHuge progress has been made in understanding the biology of innate lymphoid cells (ILC) by adopting several well-known concepts of T cell biology. As such flow cytometry gating strategies and markers, such as CD90, to identify ILC were discovered. Here we report that most non-NK intestinal ILC have a high expression of CD90 as expected, but surprisingly some have only a low or even no expression of this marker. CD90-negative CD127+ ILC were identified among all ILC subsets in the gut. CD90-negative cLP ILC2 were frequent at steady state. The frequency of CD90-negative CD127+ ILC was dependent on stimulatory cues in vitro and in vivo, and CD90-negative CD127+ ILC played a functional role as a source of IL-13, IFNγ and IL-17A at steady state and upon dextran sulphate sodium-elicited colitis. Hence, this study highlights for the first time that CD90 is not constitutively expressed by functional ILC in the gut.

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