Neuroantigen-Specific CD8+ Regulatory T-Cell Function Is Deficient During Acute Exacerbation of Multiple Sclerosis
| dc.contributor.advisor | Karandikar, Nitin J. | en |
| dc.contributor.committeeMember | Street, Nancy E. | en |
| dc.contributor.committeeMember | Thiele, Dwain L. | en |
| dc.contributor.committeeMember | Forman, James | en |
| dc.contributor.committeeMember | Greenberg, Benjamin M. | en |
| dc.creator | Baughman, Ethan James | en |
| dc.date.accessioned | 2015-07-27T16:01:35Z | |
| dc.date.created | 2013-05 | |
| dc.date.issued | 2013-05-31 | |
| dc.date.submitted | May 2013 | |
| dc.description.abstract | Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). MS is thought to be T-cell-mediated, with prior research predominantly focusing on CD4+ T-cells. There is a high prevalence of CNS-specific CD8+ T-cell responses in MS patients and healthy subjects. However, the role of neuroantigen-specific CD8+ T-cells in MS is poorly understood, with the prevalent notion that these may represent pathogenic T-cells. We show here that healthy subjects and MS patients demonstrate similar magnitudes of CD8+ and CD4+ T-cell responses to various antigenic stimuli. Interestingly, CD8+ T-cells specific for CNS autoantigens, but not those specific for control foreign antigens, exhibit immune regulatory ability, suppressing proliferation of CD4+CD25- T-cells when stimulated by their cognate antigen. While CD8+ T-cell-mediated immune suppression is similar between healthy subjects and clinically quiescent treatment-naïve MS patients, it is significantly deficient during acute exacerbation of MS. Of note, the recovery of neuroantigen-specific CD8+ T-cell suppression correlates with disease recovery post-relapse. In healthy adult subjects, we observed that the CD62L- subset of CD8+ T cells harbored increased CNS- and Copaxone-specific suppressive ability, when compared to the CD62L+ subset and bulk CD8+ T cells, and that the CD28+ subset of CD8+ T cells harbored increased global suppressive ability, when compared to the CD28- subset. In contrast, we observed CD8+ T cells from neonates harbored increased global suppressive ability in the CD28- subset. The mechanism of neuroantigen-specific suppression by CD8+ T cells was dependent upon HLA class I, IFN gamma, with possible partial involvement by NKG2D, PD-1, and IL-10. These studies reveal a novel immune suppressor function for neuroantigen-specific CD8+ T-cells that is clinically relevant in the maintenance of peripheral tolerance and the intrinsic regulation of MS immune pathology. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 914484579 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/1703 | |
| dc.language.iso | en | en |
| dc.subject | Autoantigens | en |
| dc.subject | CD8-Positive T-Lymphocytes | en |
| dc.subject | Multiple Sclerosis | en |
| dc.subject | T-Lymphocytes, Regulatory | en |
| dc.title | Neuroantigen-Specific CD8+ Regulatory T-Cell Function Is Deficient During Acute Exacerbation of Multiple Sclerosis | en |
| dc.type | Thesis | en |
| dc.type.material | Text | en |
| thesis.date.available | 2015-06-01 | |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Immunology | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |