Aggor, FEY
(2020)
MECHANISTIC INSIGHTS INTO THE ROLES OF IL-22/IL-22RA1 AXIS IN ORAL ANTIFUNGAL IMMUNITY.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Oropharyngeal candidiasis (OPC, oral thrush) is an opportunistic infection caused by the commensal fungus Candida albicans. IL-17 and IL-22 are produced by Type 17 lymphocytes.Both cytokines mediate antifungal immunity yet activate quite distinct downstream signaling
pathways. While much is now understood about how IL-17 promotes immunity in OPC, the activities of IL-22 are far less well delineated. In this dissertation, I focused on identifying mechanisms by which IL-22 mediates oral antifungal immunity. In chapters 3 and 4, I identified
key differences between IL-22 and IL-17-dependent antifungal events during innate OPC response. We show that, despite having similar requirements for induction from Type 17 cells, IL-22 and IL-17 function non-redundantly during OPC. We find that the IL-22 and IL-17 receptors are required in anatomically distinct locations within the oral mucosa; loss of IL-22RA1 or STAT3 in the oral basal epithelial layer (BEL) causes susceptibility to OPC, whereas IL-17RA is needed in the suprabasal epithelial layer (SEL). Transcriptional profiling of the tongue linked IL22/STAT3 to oral epithelial cell proliferation and survival, but also, unexpectedly, to driving an IL-17-specific gene signature. We show that IL-22 mediates regenerative signals on the BEL that replenish the IL-17RA-expressing SEL, thereby restoring the ability of the oral epithelium to
respond to IL-17 and thus to mediate antifungal events. Consequently, IL-22 signaling in BEL ‘licenses’ IL-17 signaling in the oral mucosa, revealing spatially distinct yet cooperative activities of IL-22 and IL-17 in oral candidiasis. In chapter 5, I assessed the roles of IL-22 in T cell recall OPC settings. IL-22 is protective in the adaptive response against OPC although the contribution
of innate IL-22-mediated responses could not be ruled out. While IL-22 deficiency resulted in cervical lymph node (cLN) hypertrophy, there was no evidence of C. albicans translocation to the cLN or increased proliferative expansion of Th17 cells. Loss of IL-22 resulted in increased Th17(CD4+IL-17A+) but decreased Th1(CD4+IFN-+) frequency. Hence IL-22 may be acting on the cLN stroma to modulate T cell responses in recall OPC settings. Our findings have implications for antifungal vaccine design strategies and oral immunosurveillance mechanisms against oral
pathologies and extra-oral diseases.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
21 September 2020 |
| Date Type: |
Publication |
| Defense Date: |
15 July 2020 |
| Approval Date: |
21 September 2020 |
| Submission Date: |
11 August 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
157 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Chronic mucocutaneous candidiasis, primary immunodeficiency syndromes, Interleukin 17, Interleukin 22, STAT3 |
| Date Deposited: |
21 Sep 2020 15:02 |
| Last Modified: |
21 Sep 2020 15:02 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/39740 |
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