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Date of Award

Spring 5-15-2016

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Group 1 ILCs produce IFN-g, express the T-box transcription factors (TFs) Eomes and/or T-bet, and are positive for the cytotoxicity receptors NK1.1 and NKp46. This population is composed of at least two cell types, NK cells and ILC1, which are distinguished by their developmental origins and requirements. The mouse salivary glands (SG) contain a large population of NK1.1 + cells which are IL-15 dependent but only minimally produce IFN-g. Our studies reveal that NK1.1 + cells in the SG represent a novel population of tissue resident Eomes + ILC1 (Chapter 2). SG ILC1 expressed markers indicative of tissue residency and have alternative functionality through the expression of the death inducing ligand TRAIL as well as CD39 and CD73 which can generate adenosine from ATP. SG ILC1 had distinct requirements for the TFs NFIL3, Eomes, and T-bet compared to both NK cells and Eomes - ILC1. Whole genome microarray confirmed that SG ILC1 were a separate population in addition to revealing that they expressed genes found in both NK cells and Eomes - ILC1. We also found that the distinguishing properties of SG ILC1 were dependent on TGF-b (Chapter 3). Loss of TGF-b signaling resulted in SG ILC1 becoming phenotypically and functionally similar to NK cells while TGF-b exposure caused NK cells to upregulate SG ILC1 markers. Mechanistically TGF-b repressed the expression of Eomes which acted to promote NK cell markers and limit TGF-b imprinting. TGF-b acted through a non-canonical Smad4-independent pathway which partially depended on JNK signaling. TGF-b mediated SG ILC1 differentiation occurred in an age dependent manner which mirrored SG development. Human SG also harbor a cell population which express markers reminiscent of mouse SG ILC1. Taken together, these studies have expanded the group 1 ILC family to include the TGF-b imprinted, Eomes + SG ILC1.

Language

English (en)

Chair and Committee

Marco Colonna

Committee Members

Wayne Yokoyama, Thad Stappenbeck, Tony French, Gene Oltz,

Comments

Permanent URL: http://dx.doi.org/10.7936/K7Z036FC

Available for download on Friday, May 15, 2116

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