Indiana University-Purdue University Indianapolis (IUPUI) / Asthma is a chronic inflammatory lung disease with intermittent flares
predominately mediated through memory T cells. The majority of the T cells in tissues
such as the lung are tissue-resident memory (Trm) cells, defined as cells that maintain
long-lasting presence in the tissue and have rapid functional recall following challenge.
Allergen-specific CD4 T helper cells that secrete the cytokine IL-9 have been shown to
be a necessary component of asthma pathogenesis. However, the precise characterization
and function of IL-9-secreting CD4+ cells (Th9 cells) are unknown. Here we
demonstrate that IL-9 production is progressively lost in Th9 cells over several rounds of
culture and that environmental cues dictate the instability or effector function of the Th9
phenotype. We show Th9 cells are long-lived tissue-resident cells with the capacity to
rapidly respond to secondary allergen challenge causing allergic airway disease (AAD).
We found in a memory model of Aspergillus fumigatus challenge, Th9 cells maintain
tissue residency throughout a 12-week period of antigen-free rest. Additionally, we
demonstrated increased frequency of IL-9-producing cells and quantity of IL-9 upon rechallenge,
characteristic of a secondary response. Antibody blockade of IL-9
immediately prior to the recall challenge significantly reduced overall allergic lung
inflammation, suggesting that IL-9 plays an obligate role in the allergic memory response following pulmonary allergen challenge. The protection afforded by IL-9 antibody
blockade was not seen in a chronic model asthma-like disease demonstrating IL-9 has a
specific role in allergic memory responses. Interestingly, IL-9-secreting cells have a
polyfunctional multi-cytokine phenotype demonstrating a highly pathogenic state that we
reproduced in culture. These observations suggest that IL-9 from Trm cell populations
and Th9 cells play a novel role in allergen recall responses and are potential therapeutic
targets for patients suffering from chronic intermittent asthma. / 2022-05-05
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/25996 |
| Date | 04 1900 |
| Creators | Ulrich, Benjamin Joseph |
| Contributors | Kaplan, Mark H., Dent, Alexander L., Srour, Edward F., Tepper, Robert S. |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
Page generated in 0.0017 seconds