Steroid-resistant human inflammatory ILC2s are marked by CD45RO and elevated in type 2 respiratory diseases

2021 ◽  
Vol 6 (55) ◽  
pp. eabd3489
Author(s):  
Esmee K. van der Ploeg ◽  
Korneliusz Golebski ◽  
Menno van Nimwegen ◽  
Joannah R. Fergusson ◽  
Balthasar A. Heesters ◽  
...  
Keyword(s):  
Therapy Resistance ◽  
Lymphoid Cells ◽  
Metabolic Reprogramming ◽  
Mucosal Tissue ◽  
Steroid Resistant ◽  
Type 2 Cytokines ◽  
Group 2 ◽  
Severe Type ◽  
Combined Data

Group 2 innate lymphoid cells (ILC2s) orchestrate protective type 2 immunity and have been implicated in various immune disorders. In the mouse, circulatory inflammatory ILC2s (iILC2s) were identified as a major source of type 2 cytokines. The human equivalent of the iILC2 subset remains unknown. Here, we identify a human inflammatory ILC2 population that resides in inflamed mucosal tissue and is specifically marked by surface CD45RO expression. CD45RO+ ILC2s are derived from resting CD45RA+ ILC2s upon activation by epithelial alarmins such as IL-33 and TSLP, which is tightly linked to STAT5 activation and up-regulation of the IRF4/BATF transcription factors. Transcriptome analysis reveals marked similarities between human CD45RO+ ILC2s and mouse iILC2s. Frequencies of CD45RO+ inflammatory ILC2 are increased in inflamed mucosal tissue and in the circulation of patients with chronic rhinosinusitis or asthma, correlating with disease severity and resistance to corticosteroid therapy. CD45RA-to-CD45RO ILC2 conversion is suppressed by corticosteroids via induction of differentiation toward an immunomodulatory ILC2 phenotype characterized by low type 2 cytokine and high amphiregulin expression. Once converted, however, CD45RO+ ILC2s are resistant to corticosteroids, which is associated with metabolic reprogramming resulting in the activation of detoxification pathways. Our combined data identify CD45RO+ inflammatory ILC2s as a human analog of mouse iILC2s linked to severe type 2 inflammatory disease and therapy resistance.

scholarly journals TNF Induces the Production of Type 2 Cytokines in Human Group 2 Innate Lymphoid Cells

2019 ◽  
Vol 143 (2) ◽  
pp. AB1
Author(s):  
Atsushi Kato ◽  
Noriko Ogasawara ◽  
Julie A. Poposki ◽  
Aiko I. Klingler ◽  
Kathryn E. Hulse ◽  
...  
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Human Group ◽  
Type 2 Cytokines ◽  
Group 2

scholarly journals IL-10 Prevents the Production of Type 2 Cytokines in Human Group 2 Innate Lymphoid Cells

2017 ◽  
Vol 139 (2) ◽  
pp. AB14
Author(s):  
Noriko Ogasawara ◽  
Julie A. Poposki ◽  
Aiko I. Klingler ◽  
Bruce K. Tan ◽  
Kathryn E. Hulse ◽  
...  
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Human Group ◽  
Type 2 Cytokines ◽  
Group 2

scholarly journals IL-10, TGF-β, and glucocorticoid prevent the production of type 2 cytokines in human group 2 innate lymphoid cells

2018 ◽  
Vol 141 (3) ◽  
pp. 1147-1151.e8 ◽  
Author(s):  
Noriko Ogasawara ◽  
Julie A. Poposki ◽  
Aiko I. Klingler ◽  
Bruce K. Tan ◽  
Ava R. Weibman ◽  
...  
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Human Group ◽  
Type 2 Cytokines ◽  
Group 2

scholarly journals Tissue-specific pathways extrude activated ILC2s to disseminate type 2 immunity

2020 ◽  
Vol 217 (4) ◽  
Author(s):  
Roberto R. Ricardo-Gonzalez ◽  
Christoph Schneider ◽  
Chang Liao ◽  
Jinwoo Lee ◽  
Hong-Erh Liang ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymphoid Cells ◽  
Nippostrongylus Brasiliensis ◽  
Tissue Specific ◽  
Type 2 Cytokines ◽  
Receptor Profile ◽  
Small Intestinal ◽  
Group 2 ◽  
Specific Tissue

Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells prominent at barrier sites. Although precursors are found in blood, mature ILC2s can enter the circulation after small intestinal perturbation by migratory helminths and move to distant tissues to influence the local reparative response. Using fate-mapping and methods to bypass the lung or intestinal phases of Nippostrongylus brasiliensis infection, we show that blood ILC2s comprise heterogeneous populations derived from distinct tissues that are dependent on alarmins matched to the receptor profile of the specific tissue ILC2s. Activation of local ILC2s by tissue-specific alarmins induced their proliferation, lymph node migration, and blood dissemination, thus systemically distributing type 2 cytokines. These studies uncover a possible mechanism by which local innate responses transition to systemic type 2 responses by extrusion of activated sentinel ILC2s from tissue into the circulation.

scholarly journals TNF induces production of type 2 cytokines in human group 2 innate lymphoid cells

2020 ◽  
Vol 145 (1) ◽  
pp. 437-440.e8 ◽  
Author(s):  
Noriko Ogasawara ◽  
Julie A. Poposki ◽  
Aiko I. Klingler ◽  
Bruce K. Tan ◽  
Kathryn E. Hulse ◽  
...  
Keyword(s):  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Human Group ◽  
Type 2 Cytokines ◽  
Group 2

scholarly journals Innate Type 2 Responses to Respiratory Syncytial Virus Infection

Viruses ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 521 ◽  
Author(s):  
Allison E. Norlander ◽  
R. Stokes Peebles
Keyword(s):  
Respiratory Syncytial Virus ◽  
High Mobility ◽  
The United States ◽  
Lymphoid Cells ◽  
Therapeutic Implications ◽  
Type 2 Cytokines ◽  
Group 2 ◽  
Syncytial Virus ◽  
Tract Infections

Respiratory syncytial virus (RSV) is a common and contagious virus that results in acute respiratory tract infections in infants. In many cases, the symptoms of RSV remain mild, however, a subset of individuals develop severe RSV-associated bronchiolitis. As such, RSV is the chief cause of infant hospitalization within the United States. Typically, the immune response to RSV is a type 1 response that involves both the innate and adaptive immune systems. However, type 2 cytokines may also be produced as a result of infection of RSV and there is increasing evidence that children who develop severe RSV-associated bronchiolitis are at a greater risk of developing asthma later in life. This review summarizes the contribution of a newly described cell type, group 2 innate lymphoid cells (ILC2), and epithelial-derived alarmin proteins that activate ILC2, including IL-33, IL-25, thymic stromal lymphopoietin (TSLP), and high mobility group box 1 (HMGB1). ILC2 activation leads to the production of type 2 cytokines and the induction of a type 2 response during RSV infection. Intervening in this innate type 2 inflammatory pathway may have therapeutic implications for severe RSV-induced disease.

scholarly journals Dichotomous metabolic networks govern human ILC2 proliferation and function

2021 ◽  
Author(s):  
Laura Surace ◽  
Jean-Marc Doisne ◽  
Carys A. Croft ◽  
Anna Thaller ◽  
Pedro Escoll ◽  
...  
Keyword(s):  
Amino Acids ◽  
Metabolic Networks ◽  
Mammalian Target Of Rapamycin ◽  
Immune Defense ◽  
Lymphoid Cells ◽  
Interleukin 33 ◽  
Type 2 Cytokines ◽  
Group 2 ◽  
And Function

AbstractGroup 2 innate lymphoid cells (ILC2s) represent innate homologs of type 2 helper T cells (TH2) that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited, and its key regulators are unknown. Here, we show that circulating ‘naive’ ILC2s have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than natural killer (NK) cells. Accordingly, ILC2s are severely reduced in individuals with mitochondrial disease (MD) and impaired OXPHOS. Metabolomic and nutrient receptor analysis revealed ILC2 uptake of amino acids to sustain OXPHOS at steady state. Following activation with interleukin-33 (IL-33), ILC2s became highly proliferative, relying on glycolysis and mammalian target of rapamycin (mTOR) to produce IL-13 while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2s, offering new strategies to target ILC2s in disease settings.

scholarly journals Role of Group 2 Innate Lymphocytes in Aspirin-exacerbated Respiratory Disease Pathogenesis

2018 ◽  
Vol 32 (1) ◽  
pp. 7-11 ◽  
Author(s):  
Andrew A. White ◽  
Taylor A. Doherty
Keyword(s):  
Respiratory Disease ◽  
Lymphoid Cells ◽  
Disease Pathogenesis ◽  
Aspirin Exacerbated Respiratory Disease ◽  
Type 2 Cytokines ◽  
Group 2 ◽  
Innate Lymphocytes ◽  
Cox 1

Aspirin-exacerbated respiratory disease (AERD) is characterized by chronic eosinophilic nasal polyps, asthma, and airway reactions upon cyclooxygenase (COX) 1 inhibition. AERD is present in up to 7% of adult patients with asthma and the underlying pathogenesis remains largely elusive but prostaglandin D2, cysteinyl leukotrienes, mast cells, and type 2 cytokines are thought to contribute. A wealth of studies have recently implicated group 2 innate lymphoid cells (ILC2), a novel lineage-negative lymphocyte population that produces type 2 cytokines, in human allergic disease pathogenesis. Importantly, our recent work identified that ILC2s are recruited to the nasal mucosa of patients on AERD after COX-1 inhibitor administration. Here, we review the potential impact of ILC2s in the development and propagation of type 2 inflammation in AERD.

scholarly journals ICAM-1 controls development and function of ILC2

2018 ◽  
Vol 215 (8) ◽  
pp. 2157-2174 ◽  
Author(s):  
Ai-Hua Lei ◽  
Qiang Xiao ◽  
Gao-Yu Liu ◽  
Kun Shi ◽  
Qiong Yang ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Allergic Airway Inflammation ◽  
Lymphoid Cells ◽  
Peripheral Tissues ◽  
Type 2 Cytokines ◽  
Functionally Impaired ◽  
Group 2 ◽  
And Function

Group 2 innate lymphoid cells (ILC2s) are emerging as key players in the pathogenesis of allergic airway inflammation. The mechanisms regulating ILC2, however, are not fully understood. Here, we found that ICAM-1 is required for the development and function of ILC2. ICAM-1–deficient (ICAM-1−/−) mice displayed significantly lower levels of ILC2s in the bone marrow and peripheral tissues than wild-type controls. CLP transfer and in vitro culture assays revealed that the regulation of ILC2 by ICAM-1 is cell intrinsic. Furthermore, ILC2s from ICAM-1−/− mice were functionally impaired, as indicated by the diminished production of type-2 cytokines in response to IL-33 challenge. The reduction in lung ILC2s caused a clear remission of airway inflammation in ICAM-1−/− mice after administration of papain or Alternaria alternata. We further demonstrate that ILC2 defects caused by ICAM-1 deficiency are due to ERK signaling-dependent down-regulation of GATA3 protein. Collectively, these observations identify ICAM-1 as a novel regulator of ILC2.

scholarly journals A stromal cell niche sustains ILC2-mediated type-2 conditioning in adipose tissue

2019 ◽  
Vol 216 (9) ◽  
pp. 1999-2009 ◽  
Author(s):  
Batika M.J. Rana ◽  
Eric Jou ◽  
Jillian L. Barlow ◽  
Noe Rodriguez-Rodriguez ◽  
Jennifer A. Walker ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Immune Cells ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Cell Stress ◽  
Lymphoid Cells ◽  
Type 2 Cytokines ◽  
Group 2 ◽  
Cell Niche

Group-2 innate lymphoid cells (ILC2), type-2 cytokines, and eosinophils have all been implicated in sustaining adipose tissue homeostasis. However, the interplay between the stroma and adipose-resident immune cells is less well understood. We identify that white adipose tissue–resident multipotent stromal cells (WAT-MSCs) can act as a reservoir for IL-33, especially after cell stress, but also provide additional signals for sustaining ILC2. Indeed, we demonstrate that WAT-MSCs also support ICAM-1–mediated proliferation and activation of LFA-1–expressing ILC2s. Consequently, ILC2-derived IL-4 and IL-13 feed back to induce eotaxin secretion from WAT-MSCs, supporting eosinophil recruitment. Thus, MSCs provide a niche for multifaceted dialogue with ILC2 to sustain a type-2 immune environment in WAT.

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