Kobayashi, Takao

Abstract Description The immunological mechanism involved in regulation of chronic airway inflammation in allergic asthma is not fully understood. This study aimed to identify subpopulation(s) of T regulatory (Treg) cell responsible for controlling type 2 airway inflammation. Treg cells in the lung tissues of fungal allergen Alternaria-exposed mice expressed higher levels of Il2ra, Pdcd1, Ctla4, Il10 as compared to those in mediastinal lymph nodes. Mass cytometry analysis identified several populations of Treg cells including the one highly expressed CCR8, ST2, and GATA-3. CCR8+ST2+ Treg cells expanded after 4-week of Alternaria exposure and persisted in the lung tissues for additional 8 weeks without allergen re-exposure; their tissue residency was not affected by FTY720 treatment. Transcriptional analysis showed that CCR8+ST2+ Treg cells were enriched for Gata3 while minimally expressed type 2 cytokines. Moreover, CCR8+ST2+ Treg cells produced higher levels of IL-10 and amphiregulin compared to CCR8-ST2+ Treg cells and effectively suppressed proliferation of effector T cells. Severe airway inflammation and asthma-like pathology developed in Treg cell-deficient (Foxp3DTR) and Ccr8-/- mice underscored the functional significance of CCR8+ST2+ Treg cells to control airway inflammation in vivo. These findings suggest that heterogenous populations of Treg cells develop in the lung tissues during chronic airway inflammation and CCR8+ST2+ Treg subpopulation is likely to be highly suppressive. Funding Sources Supported by NIH grant R37 AI71106; Mayo Foundation; Mayo Graduate School of Biomedical Sciences Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)

Abstract CD8+ T cells represent a relatively under studied cell type in allergic lung inflammation, despite their presence in the mucosal tissues. This is because CD8+ T cells are normally associated with a Th1 response as opposed to Th2 or Th17 responses, as are the most cases with allergic inflammation. However, recent papers have shown the production of Th2 and Th17 cytokines in these cells, yet knowledge of their physiological role in allergic inflammation is incomplete. The presence of IL-17 in asthma patients contributes to a severe, steroid resistant phenotype. Therefore, determining contributors of IL-17 and their physiological role is paramount to understanding the disease. Our preliminary data which suggests memory Tc17 cells are generated in CD4-/- mice when sensitized intranasally to ovalbumin with IL-33. We believe Tc17 cells are responsible for the inflammation because the inflamed lung tissue contained elevated IL-17, and stimulated T cells from inflamed tissue produced elevated levels of IL-17 as well. Additionally, we were unable to induce inflammation in Rag-/- mice or TCRβ-/- mice, which pinpoints the cell responsible to CD8+ T cells in CD4-/- mice. Using these mice to study an exaggerated phenotype will allow us to more easily detect the contributions that happen to a lesser degree in wild type animals. This work create a more complete picture of the disease environment and lead to therapies which can account for the contribution of this cell type.