Research Assistant Professor Indiana Univ. Sch. of Med. indianapolis, Indiana, United States
Introduction/Rationale: Chronic allergic airway inflammation results in the establishment of a tissue resident memory T (Trm) cell population that can respond to subsequent allergen challenge. A subset of multi cytokine-producing CD4+ Trms that express high levels of IL-9 with type 2 cytokines, is critical to mediate this rapid allergen recall responses upon challenge. PU.1 (Spi1), BCL6, PPARγ, BATF, and IRF4 have been shown to be important in IL-9 expression in Th9 cells, but their role in generating a multi-cytokine phenotype in Trm cells has not been investigated.
Methods: We used a memory-recall model of chronic allergic lung inflammation that mimics seasonal allergies with house dust mite (HDM) sensitization to challenge wild-type, Spi1 fl/fl iCD4-Cre, Spi1 fl/fl CD4-Cre, and Bcl6 fl/fl iCD4-Cre mice to study the reciprocal roles of PU.1 and BCL6. Mice were challenged intranasally three times a week for 6 weeks with HDM followed by a 6-week rest period absent of any allergen challenge. Mice with inducible CD4-Cre were treated with tamoxifen for the last two weeks of the allergen-free period. Mice were then challenged with HDM 2 day before analysis.
Results: Deletion of PU.1 resulted in decreased Trms and IL-9, IL-13 production and diminished eosinophilic inflammation in the memory response in lung in vivo. However, deletion of BCL6 from CD4+ T cells resulted in increased Trms and increased IL-9 and IL-13 production and eosinophilic inflammation in the lung in vivo.
Conclusion: Our results show that during allergic airway inflammation, BCL6 and PU.1 play reciprocal roles in regulating tissue resident T cells and multi-cytokine-producing Th9 cell population that mediates the memory-recall in allergic lung inflammation.
