Thymic Atrophy Impairs the Development and Function of an Antigen-Specific Treg Clone

Simple item page
dc.contributor.advisorSu, Dong-Ming
dc.contributor.committeeMemberBerg, Rance E.
dc.contributor.committeeMemberMathew, Stephen O.
dc.contributor.committeeMemberMathew, Porunelloor A.
dc.contributor.committeeMemberSchreihofer, Ann M.
dc.creatorThomas, Rachel R.
dc.date.accessioned2021-12-16T21:15:11Z
dc.date.available2021-12-16T21:15:11Z
dc.date.issued2021-05
dc.description.abstractAge-related thymic atrophy results in dysfunctional ɑβ-T cell selection, exhibited by reduced output of naïve conventional T (Tcon) cells coupled with a contraction of the T cell receptor (TCR) repertoire. This opens "holes" or "windows" in the effector T (Teff) repertoire allowing for infection. However, the impact of the aged thymus on the CD4+FoxP3+ regulatory T (Treg) TCR repertoire, important for self-tolerance, is insufficiently understood. Given evidence that thymic Treg (tTreg) cell generation is relatively enhanced in the aged, atrophied thymus, and that the aged periphery accumulates peripheral Treg (pTreg) cells, we investigated why these Treg cells are unable to effectively attenuate the increased auto-reactivity-induced chronic inflammation (inflammaging) in the elderly. We designed a mock self-antigen (membrane-bound ovalbumin, mOVA) chimeric mouse model, bearing a FoxN1-floxed gene for induction of conditional thymic atrophy, that received OVA-specific (OT-II) TCR transgenic progenitor cells. We observed a significant decrease in OVA-specific tTreg and pTreg cells, but not polyclonal (pan)-Treg cells, in mice with thymic atrophy compared to controls. Further, the OVA-specific pTreg cells from mice with thymic atrophy demonstrated significant reduction in the ability to suppress OVA-specific stimulation-induced proliferation in vitro, and exhibited lower FoxP3 expression. In our TCR repertoire diversity sequencing for Treg cells among recent thymic emigrants (RTEs) from RagGFP-FoxP3RFP dual reporter mice, we observed a trend for decreased TCR diversity in mice with thymic atrophy compared to littermates with normal thymus. These data indicate that although the effects of age-related thymic atrophy do not affect pan-Treg generation, certain tissue-specific Treg clones may experience abnormal agonist selection, likely creating TCR repertoire holes in the aged T cell regulatory system. Taken together, our findings suggest that altered Treg cell development in the atrophied thymus and subsequent functional defects likely contribute to age-related chronic inflammation, even in the absence of acute autoimmune disease in the elderly.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/30766
dc.language.isoen
dc.subjectthymic involution
dc.subjectregulatory T (Treg) cell
dc.subjectTCR diversity
dc.subjectinflammaging
dc.subject.meshAtrophy
dc.subject.meshThymus Gland
dc.subject.meshT-Lymphocytes, Regulatory
dc.subject.meshInflammation / immunology
dc.titleThymic Atrophy Impairs the Development and Function of an Antigen-Specific Treg Clone
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineBiomedical Sciences
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
2021_05_gsbs_Thomas_Rachel_dissertation.pdf
Size:
3.72 MB
Format:
Adobe Portable Document Format
Description:
Download

Collections

School of Biomedical Sciences
Theses and Dissertations