IL-25 has been established as a regulator of type 2 inflammation and multiple reports have described its ability to exacerbate inflammatory responses at mucosal epithelia, including those in allergic asthma. The present study used a mouse model of chronic allergic asthma to identify both T and non-T IL-25 responsive cells involved in pulmonary inflammation. While previous studies have established that targeting IL-25 leads to the reduction of type 2 responses22,23
, this study is the first to characterize how deficiency in IL-17RB reduces the pathology of allergic asthma induced by a common environmental allergen. Other reports, including one from our laboratory, have demonstrated that eosinophils produce IL-257,8
, thus linking IL-25 production to eosinophilia induced by the allergic response. These data are consistent with clinical studies, as peripheral blood mononuclear cells from patients with severe allergic rhinitis exhibit increased IL-17RB24
, and polymorphisms in IL-17RB have been associated with increased risk for severe asthma25
. Furthermore, a recent study has identified that allergen-induced expression of IL-25 and its receptor in atopic asthmatics correlates with disease severity21
mice had reduced allergen-induced pathology, including a significant reduction in type 2 cytokines primarily associated with T2M cells that were most prominent during persistent allergen-induced disease. The transfer of IL-25-induced T2M cells recapitulated lung pathology in IL-25 treated Il17rb−/−
mice, demonstrating the sufficiency of T2M cells to mediate pathogenic responses. T2M cells appear to be steroid resistant in vivo
and represent a distinct granulocytic population, which may have been identified in a model of pulmonary inflammation during N. brasiliensis
. T cell function was also altered in Il17rb−/−
mice, demonstrating that in chronic allergic disease both T cell and non-T cell populations are contributors to type 2 cytokine-mediated pathophysiology.
While T lymphocytes are responsible for driving allergen-specific type 2 responses, multiple reports have identified critical roles for innate immune populations. Models of N. brasiliensis
infection have identified novel IL-25 responsive cells in the gut, characterized as Lin−
, that play an important role in the clearance of enteric helminthes18–20
. Recent studies have identified a similar innate lymphocytic cell population in the gut, lung, and nasal polyps of humans, further supporting their potential role in human disease27
. In our studies, this population was present at low numbers in the lung, and did not increase following allergen or IL-25 administration. Previous reports have identified other non-lymphoid populations as sources of type 2 cytokines that can contribute to the allergic environment, including basophils, mast cells, eosinophils, and macrophages28–38
. We did not detect significant IL-17RB expression in any of these populations in the lungs of allergen challenged animals. Thus, it appears that there are both Lin+
IL-25 responsive cells whose recruitment may depend upon the type of mucosal surface (gut versus lung), both with the capacity to produce type 2 cytokines in an antigen-independent manner.
Analysis of surface markers and presence in the bone marrow during allergen and IL-25-induced responses indicate that T2M cells are derived from the bone marrow. Their presence in peripheral blood of humans with asthma may represent an induced cell population that may be recruited and accumulate in the lung during persistent or exacerbated disease. Because IL-17RB+
subsets could be distinguished based upon the intensity of Gr-1 expression, and in light of the differing capacity for IL-4 and IL-13 production between Gr-1mid
cells may have functions that overlap with other CD11b+
populations, such as myeloid suppressor cells39,40
. A recent study reported that both IL-17RA and IL-17RB can be expressed on the surface of human neutrophils41
. Clinical studies of patients with steroid resistant asthma demonstrated that a neutrophilic inflammatory response is predominant, while animal studies have suggested that steroid resistant Th17 cells may explain neutrophil-mediated responses42–50
. Since IL-17RA is required for functional IL-17A and IL-25 signaling, these cytokines may share downstream signals induced following ligand binding that provide a common link for steroid resistance. The development of T2M cells likely depends upon an overall type 2 immune environment and perhaps IL-25 itself.
Our data also indicate that, based on the rapid accumulation of myeloid cells in lungs following IL-25 administration, there is a pool of cytokine producing IL-25 responsive cells capable of amplifying a type 2 response. In allergic individuals, T2M cells may play an important role in the immediate response to an environmental allergen, priming the system for a type 2 response by producing cytokines prior to T lymphocyte activation. T2M cells could also contribute to chronic disease, as airway epithelial damage stimulates IL-25 secretion. This concept may be especially relevant in asthmatics, as our studies identified increased numbers of T2M-like cells in circulation of asthmatics that may be recruited upon an exacerbation and accumulate in the lungs. The induction of IL-25 in airways by pathogens51
, allergens, or other noxious stimuli may amplify the severity of the response by activating steroid resistant T2M cells, especially in patients with underlying pulmonary disease. A complete understanding of the development and function of T2M cells will require further investigation, however our findings suggest that they represent an intriguing biomarker and possible therapeutic target for the treatment of severe asthma.