Interleukin-33 activates regulatory T cells to suppress innate γδ T cell responses in the lung

Abstract

Foxp3 + regulatory T (T reg ) cells expressing the interleukin (IL)-33 receptor ST2 mediate tissue repair in response to IL-33. Whether T reg cells also respond to the alarmin IL-33 to regulate specific aspects of the immune response is not known. Here we describe an unexpected function of ST2 + T reg cells in suppressing the innate immune response in the lung to environmental allergens without altering the adaptive immune response. Following allergen exposure, ST2 + T reg cells were activated by IL-33 to suppress IL-17-producing γδ T cells. ST2 signaling in T reg cells induced Ebi3, a component of the heterodimeric cytokine IL-35 that was required for T reg cell-mediated suppression of γδ T cells. This response resulted in less eosinophil-attracting chemokines and reduced eosinophil recruitment into the lung, which was beneficial to the host in reducing inflammation induced by allergen. Thus, we define a fundamental role for ST2 + T reg cells in the lung as a negative regulator of the early innate γδ T cell response to mucosal injury.

An immune-based biomarker signature is associated with mortality in COVID-19 patients

“…S100A9; LBP; soluble ST2 (sST2), which serves as a decoy receptor for IL-33; and RAGE (also known as AGER) have been used as prognostic biomarkers in sepsis ( 48 – 53 ). sST2 levels were increased in COVID-19 patients and were strongly correlated with disease severity, with marked elevations seen in patients who died ( Figure 4 and Supplemental Table 3 ).…”

Single-cell analysis uncovers differential regulation of lung γδ T cell subsets by the co-inhibitory molecules, PD-1 and TIM-3

“…Lung γδ T cells – particularly the IL-17A-producing cells – play important roles in homeostasis, infection, inflammation, allergy, cancer progression and metastasis (Coffelt et al, 2015; Faustino et al, 2020; Guo et al, 2018; Jin et al, 2019; Kulig et al, 2016; Misiak et al, 2017; Wang et al, 2021). However, knowledge on γδ T cell diversity, expression of distinguishing molecules and regulation within the lung is not well understood.…”

“…IL-17A-producing γδ T cells within the lung consist mostly of Vγ4 + and Vγ6 + cells that can function as either protective or pathogenic cells during infection, inflammation and allergy (Faustino et al, 2020; Guo et al, 2018; Misiak et al, 2017; Wang et al, 2021). These cells are also key drivers of lung cancer and pulmonary metastasis (Coffelt et al, 2015; Jin et al, 2019; Kulig et al, 2016).…”

Perivascular stromal cells: Directors of tissue immune niches

“…64 An unexpected role for lung Tregs in the cross-regulation of innate type 3/17 lymphocytes was also recently described. 61 Following HDM-induced allergic pulmonary inflammation, adventitial localized ST2 + Tregs were activated by IL-33 and uniquely suppressed IL-17A-producing γδ T cells via IL-35 production. 61 Similar results were shown for ST2 + Tregs in the adipose tissue and central nervous system after neuroinflammation.…”