CD4(+) T-cell cytokine production within a ay mucosal DC-T-cell clusters drives the local recruitment of myeloid effector cells in response to house dust mite allergen

Abstract Allergic asthma develops in the mucosal tissue of small bronchi. Upon allergen exposure, a TH2-type inflammatory response leads to airflow obstruction and wheezing. Recent studies provided a detailed understanding on the role of various cell types and mediators in the allergic response on the level of the whole organism or tissue. However, less well understood is the micro-anatomical organization of the key cellular players, dendritic cells (DCs) and CD4+ T cells within the airway mucosa and the mechanisms by which local T-DC interactions contribute to the ‘downstream’ inflammatory response (e.g. eosinophil recruitment). Here we utilized advanced in vivo dynamic and in situ static imaging to visualize CD4+ T-cell activation and effector function in the tracheal mucosa. Upon mucosal sensitization to house dust mite (HDM) allergen, newly recruited CD4+ T cells formed discrete cellular clusters and showed prolonged interactions with DCs in an antigen-specific manner. While forming direct cell-cell contacts with MHC-II+ DCs, a small fraction of CD4+ T cells, but not innate lymphoid cells (ILCs), produced IL-13 or IL-17. As a result of local TH2 cytokine signaling, revealed by STAT-6 phosphorylation, eosinophils were locally recruited into these cellular clusters. Neutrophils also infiltrated these clusters in a T-cell dependent manner; however, their distribution was more diffuse. Our findings reveal the focal nature of antigen-driven allergic responses in the airways and define multiple steps with potential for interference with the progression of asthmatic pathology. This work was supported in part by the Intramural Research Program of NIAID, NIH.