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ORCID

http://orcid.org/0000-0002-6678-3496

Date of Award

Summer 8-15-2020

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

STING N153S in mice and STING N154S in humans cause spontaneous autoimmunity. Specifically, these mutations reduce the numbers of T cells and NK cells, and cause lung disease. However, mice develop perivascular lung inflammation that is distinct from the pulmonary fibrosis observed in human patients. Viral infections are known to exacerbate autoimmunity and foment pulmonary fibrosis. Therefore, we hypothesized that exposure to a virus may influence STING N153S disease in mice. To test this, we infected STING N153S animals with the gammaherpesvirus family member, gHV68, and found that 14 days post infection pulmonary fibrosis was readily observed by histological staining. Furthermore, STING N153S impaired the T and B cell-mediated immune responses to gHV68. While characterizing the adaptive immune system, we discovered that STING N153S animals lacked lymph nodes and Peyer’s patches. These secondary lymphoid organs are important sites of adaptive immunity induction and absence of lymph nodes may explain some aspects of T and B cell impairment. In addition, we found fewer innate lymphoid cells including a type of innate lymphoid cell termed lymphoid tissue inducer (LTi) cells. LTi cells are required for lymph node development. We found that RORgT-Cre driven conditional expression of STING N153S in LTi cells and T cells was sufficient to prevent lymph node and Peyer’s patch organogenesis. Together, our data show that STING N153S renders mice highly immunodeficient by impairing both adaptive and innate lymphocytes and that viral infection of STING N153S mice triggers pulmonary fibrosis

Language

English (en)

Chair and Committee

Jonathan J. Miner

Committee Members

Anthony French, Megan T. Baldridge, Liang Shan, Wayne Yokoyama,

Available for download on Thursday, July 07, 2022

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