Group 2 innate lymphoid cells and CD4⁺ T cells cooperate to mediate type 2 immune response in mice

Abstract

Background Innate lymphoid cells (ILCs) play important roles in innate immunity and tissue remodeling via production of various cytokines and growth factors. Group 2 ILCs (ILC2s) were recently shown to mediate the immune pathology of asthma even without adaptive immunity. However, little is known about possible interactions between ILC2s and other immune cells. We sought to investigate the capacity of ILC2s to regulate effector functions of T cells. Methods We isolated ILC2s from the lungs of naïve mice. We cultured CD4+ T cells with ILC2s in vitro and examined the functions of these cell types. The mechanisms were investigated by using blocking antibodies and cells isolated from cytokine-deficient mice. For the in vivo study, we adoptively transferred ILC2s and CD4+ T cells into Il7ra−/− mice and subsequently exposed the mice to ovalbumin and a cysteine protease. Results Lung ILC2s enhanced CD4+ T cell proliferation and promoted production of type 2 cytokines in vitro. The interaction between ILC2s and CD4+ T cells involved costimulatory molecule OX40L and cytokine IL-4, which was mainly derived from ILC2s. Adoptive transfer of both ILC2 and CD4+ T cell populations, but not each population alone, into Il7ra−/− mice resulted in induction of a robust antigen-specific type 2 cytokine response and airway inflammation. Conclusion Lung ILC2s function to promote adaptive immunity in addition to their established roles in innate immunity. This novel function of ILC2s needs to be taken into account when considering the pathophysiology of asthma and other allergic airway diseases.

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

“…ILC2s were shown to have the capacity to enhance differentiation of naive CD4 + T cells to a Th2 phenotype while inhibiting Th1 differentiation in a contactdependent manner [16,17]. Together with analyses in helminth infection models showing that Th2 responses are impaired in the absence of ILC2s [18,19], these findings support a model in which ILC2s are "early sentinel" cells that can be rapidly activated to connect innate and adaptive immunity by acting as an early innate source of type 2 cytokines.…”

“…The ability for ILC2 to produce IL-5 and IL-13 is drastically reduced in HDM-sensitized and -challenged Il21r −/− mice, although this is not a cell-intrinsic feature, thus suggesting that IL-21 may indirectly promote ILC2s [22]. OX40-L has also been implicated in the interaction between ILC2s and T cells [17] and more recently, it was shown that ICOS:ICOS-L interaction is critical for ILC2 function through STAT5 signaling, suggesting a possible role for B cells in the maintenance of ILC2s [39]. Our study however, indicates that B cells were dispensable for the initiation of ILC2 recruitment and their proliferation.…”

ILC2s and T cells cooperate to ensure maintenance of M2 macrophages for lung immunity against hookworms

“…Recent papers have demonstrated that ILC2s are important in building a bridge between innate and adaptive immune responses, notably through MHC (major histocompatibility complex) class II interaction and antigen presentation 28,40,41 . However, in spite of the demonstration that T cells could maintain ILC2s to mediate the expulsion of Nb from the gut 10 days post infection 15 , it remained unclear whether the ILC2s could play a role in an anamnestic response.…”

Mechanisms of Experimental Mouse Models of Airway Hyperresponsiveness

“…However, as they express CD45 and are dependent on traditional T cell growth factor signaling pathways such as those mediated through the common γc-chain and IL-7 receptor-a chain (CD127), they have been called innate lymphoid cells. Numerous murine studies have now shown that ILC2-driven type 2 cytokine production is sufficient to induce allergen-mediated airway inflammation (Drake et al, 2014) and viral infection-induced AHR (Chang et al, 2011) in the absence of conventional T cells. The effects of these ILC2s on allergic inflammation are thought to be IL-13-mediated as adoptive transfer of wild-type ILC2s producing IL-13, but not IL-13 −/− cells, into IL-13-deficient mice was shown to be sufficient to induce allergic inflammation (Barlow et al, 2012).…”