THYMIC DEVELOPMENT OF AUTOREACTIVE T CELLS IN NOD MICE, AND THE ALTERED TRAFFICKING OF T CELLS FOLLOWING ANTIBODY MEDIATED CROSSLINKING OF THE CD4 CORECEPTOR Public Deposited

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  • March 19, 2019
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  • Morillon, Yves
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Two key processes in driving type 1 diabetes are the development and trafficking of &beta; cell-specific T cells into the pancreas. The first part of this dissertation examines thymic development of autoreactive T cells, whereas the second part explores novel T cell trafficking pathways upon antibody binding to CD4. The production of autoreactive T cells occurs through a failure of negative selection in the thymus. We utilized a thymic transplant approach to investigate possible ontogenic changes in autoreactive T cell production. Various aged NOD thymi were transplanted into NOD.<italic>scid<italic> recipients, which were then assessed for pathology. The development of diabetes was restricted to recipients of newborn thymi, insulitis was observed in recipients of 7 and 10 day, but not older thymi. Increased diabetes and insulitis was associated with increased diabetogenic T effectors and not with altered regulatory T cell frequency or activity. In contrast, recipients of older thymi developed colitis, characterized by IFN&gamma; and IL-17 producing T cells reactive to gut microbiota. These findings demonstrate that thymic development of autoreactive T cells is restricted to a narrow window, and that the efficacy of thymic negative and positive selection increases with age in mice. T cell migration is a highly controlled process of adaptive immunity. Defects in trafficking can result in inappropriate immune responses, including autoimmunity. We recently reported diabetes remission in NOD mice following administration of anti-CD4 and anti-CD8 antibodies. Remission was associated with T cell purging from the pancreas and pancreatic lymph nodes. In this study, we investigated the mechanisms of purging following anti-CD4 treatment. Shortly after anti-CD4 treatment, the activity of the GTPases Rac1 and Rac2 were markedly increased. Notably, Rac1 and Rac2 function are associated with T cell migration. In addition, T cell polarization was increased, and expression of lymph node homing adhesion molecules were decreased, concomitant with T cell egress from the pancreatic lymph nodes. Furthermore pancreatic lymph node but not splenic T cells isolated from anti-CD4 treated mice exhibited increased in vitro chemotaxis to tested chemokines. These findings demonstrate that crosslinking of CD4 induces a pro-migratory phenotype via a novel Rac associated pathway in T cells.
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  • In Copyright
Advisor
  • Vilen, Barbara J.
  • Su, Lishan
  • Tisch, Roland
  • Matsushima, Glenn
  • Su, Maureen
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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  • Chapel Hill, NC
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  • This item is restricted from public view for 1 year after publication.
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