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

Abstract

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.

Role of ILC2 in Viral-Induced Lung Pathogenesis

“…The role of ILC2 in asthma and airway disease has been studied recently and reviews describing their role have previously been published (79)(80)(81)(82). In severe steroid resistant asthma, ILC2 numbers correspond to the severity of disease exacerbation demonstrating a systemic effect of the disease process (83,84). The Th2 immune response has been correlated with these exacerbations and since respiratory viral infections enhance Th2 responsiveness of ILC2, it is likely that these cells play a crucial role in exacerbation of asthmatic disease (85).…”

Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD

“…Compromised by oxidative stress, airway epithelial cells are injured and lose their integrity, becoming a primary source of alarmins and DAMP in asthma and COPD [ 207 ]. Thymic stromal lymphopoietin (TSLP), a key alarmin in asthma pathogenesis, initiates Th2 responses that promote allergic airway inflammation [ 191 , 208 ] and are implicated in contributing to corticosteroid insensitivity in asthma [ 209 , 210 , 211 ]. Additionally, airway epithelial cells from COPD donors produce greater TSLP levels upon inflammatory stimulation, which was found to be insensitive to dexamethasone [ 212 ].…”

Serum Th‐2 cytokines and FEV1 decline in WTC‐exposed firefighters: A 19‐year longitudinal study

“…Prolonged alteration of IL‐4 concentration in serum could be a result of “trained immunity,” a form of innate immune memory produced by covalent histone modification in lung ILC2 cells in patients with severe asthma 26 . Notably, ILC2 cells are steroid‐resistant, which may partly explain why inhaled steroids fail to control respiratory symptoms in many WTC‐exposed firefighters 11,27–29 . Future research should assess associations of accelerated‐FEV 1 ‐decline with upstream mediators of chronic airway inflammation that modulate ILC2 activity such as TSLP and IL‐33.…”