Dampening type 2 properties of group 2 innate lymphoid cells by a gammaherpesvirus infection reprograms alveolar macrophages

Abstract

Immunological dysregulation in asthma is associated with changes in exposure to microorganisms early in life. Gammaherpesviruses (γHVs), such as Epstein-Barr virus, are widespread human viruses that establish lifelong infection and profoundly shape host immunity. Using murid herpesvirus 4 (MuHV-4), a mouse γHV, we show that after infection, lung-resident and recruited group 2 innate lymphoid cells (ILC2s) exhibit a reduced ability to expand and produce type 2 cytokines in response to house dust mites, thereby contributing to protection against asthma. In contrast, MuHV-4 infection triggers GM-CSF production by those lung ILC2s, which orders the differentiation of monocytes (Mos) into alveolar macrophages (AMs) without promoting their type 2 functions. In the context of γHV infection, ILC2s are therefore essential cells within the pulmonary niche that imprint the tissue-specific identity of Mo-derived AMs and shape their function well beyond the initial acute infection.

Shaping of the alveolar landscape by respiratory infections and long-term consequences for lung immunity

“…IL-13 is required for the early polarization and maintenance of AMs, but also MO-AMs, in an M2 state in adult mice ( 87 ). Likewise, we have recently highlighted the crucial role that pulmonary ILC2s play in conferring identity and functional polarization to MOs that differentiate into AMs during life ( 88 ). In particular, we have shown that after Murid herpesvirus 4 (MuHV-4) infection, a mouse γHV, lung ILC2s exhibit a reduced ability to produce type 2 cytokines in response to HDM, thereby contributing to protection against allergic airway inflammation.…”

“…This general skewing towards type 2 inflammation could have a direct effect on asthma susceptibility but could also have an indirect effect on the Th1/Th2 balance later in life by promoting a M2 polarization on AMs and MO-AMs for the long term. In particular, we have recently published a key role for ILC2s in conferring AM identity and polarisation after a virus-induced depletion of the alveolar niche ( 88 ). Deciphering the potential contribution of ‘M2’ AMs (or MO-AMs), trained early in life by activated ILC2s, in long-term sequelae like asthma, could be of major importance in future research.…”

Differentiation of Bone Marrow Monocytes into Alveolar Macrophages-like Cells through Co-culture with Lung Epithelial Cells and Group 2 Innate Lymphoid Cells

“…As ILC2 and epithelial cells phenotypes are directly impacted by environmental conditions, the outcome of the experiment largely depends on the environmental conditions to which mice have been subjected, as seen for example with MuHV-4 infection ( Loos et al, 2023 ).…”

“…Their role in modulating alveolar macrophage (AMs) polarization has been described in early life through the IL-33/ILC2/IL-13 activation cascade, which confers an M2 phenotype to AMs ( Saluzzo et al, 2017 ). In the context of a persistent viral infection, we recently highlighted the essential role of ILC2s as lung niche cells that imprint the tissue-specific identity of monocytes (MOs)-derived AMs and shape their function ( Loos et al, 2023 ).…”

“…In particular, this protocol describes the experimental conditions for co-culture of epithelial cells (ECs) and bone marrow MOs, with group 2 lung innate lymphoid cells (ILC2s) isolated from mouse lung. In the related publication, we showed that bone marrow MOs differentiate in vitro into AM-like cells in the presence of ILC2s and ECs, as evidenced by the expression of genes related to macrophage differentiation and activation ( Csf1, PPARg , and Il4ra ) ( Loos et al, 2023 ). In addition, we also showed the long-term effect of lung gammaherpesvirus infection on ILC2s and the subsequent consequences on ILC2-mediated differentiation of MOs into AMs.…”