Thymic involution perturbs negative selection and leads to chronic inflammation

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dc.contributor.advisorDong-Ming Su
dc.contributor.committeeMemberRance E. Berg
dc.contributor.committeeMemberHriday K. Das
dc.creatorCoder, Brandon D.
dc.date.accessioned2019-08-22T19:55:17Z
dc.date.available2019-08-22T19:55:17Z
dc.date.issued2015-08-01
dc.date.submitted2015-08-17T12:36:05-07:00
dc.description.abstractThe ubiquitous presence of chronic low-level pro-inflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality. The etiology of inflammaging is largely unknown. Recent evidence has identified the persistent activation of immune cells, thought to arise from latent viral infections, as key contributors towards the development of a chronic inflammatory environment. However, the contribution of autoreactive T cells towards the development of inflammaging has yet to be investigated. Another pervasive feature of the aging process is the age-related involution of the thymus gland, which has been linked with a predisposition toward developing autoimmunity. In the present study, we determined how age-related thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging. We utilized a FoxN1 conditional knock-out (FoxN1-cKO) mouse model that mimics thymic involution while maintaining a young periphery and naturally aged C57Bl/6 mice. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by cellular infiltration into non-lymphoid tissues, elevated serum IL-6, and enhanced production of TNFα. Additionally, activated autoreactive T cell clones were detected in the periphery of FoxN1-cKO mice. We determined that a failure of negative selection, facilitated by decreased AIRE expression rather than impaired regulatory T cell (Treg) generation, and led to autoreactive T cell activation in the periphery. Furthermore, we have demonstrated that the young environment can reverse the age-related accumulation of Tregs but not inflammatory infiltration. Together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a source of chronic age-related inflammation (inflammaging).
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/27291
dc.language.isoen
dc.provenance.legacyDownloads215
dc.subjectHemic and Immune Systems
dc.subjectImmunology and Infectious Disease
dc.subjectImmunopathology
dc.subjectMedical Sciences
dc.subjectMedicine and Health Sciences
dc.subjectPathological Conditions, Signs and Symptoms
dc.subjectTissues
dc.subjectthymus
dc.subjectinflammation
dc.subjectimmunology
dc.subjectautoimmunity
dc.titleThymic involution perturbs negative selection and leads to chronic inflammation
dc.typeDissertation
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

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