Regulatory mechanisms controlling T cell activity

Research output: ThesisDoctoral Thesis (compilation)

Abstract

This thesis is based on work studying the immunoregulatory mechanisms that govern the balance between activation and inactivation of T lymphocytes. Most of the work has been carried out in an experimental system using a T cell receptor (TCR-Vb3) transgenic mouse strain to obtain a homogenous T-cell population and utilizing the properties of bacterial superantigens to induce T cell responses and unresponsiveness in vivo. Injection of the superantigen staphylococcal enterotoxin A (SEA) to TCR-Vb3 transgenic mice activates both CD4+ and CD8+ T cells, large amounts of proinflammatory cytokines are produced within hours of injection and the responding T cell-population is expanded in number. In addition, CD8+ T cells differentiate into cytotoxic T cells (CTL). However, repeated injections of the same superantigen induces a state of unresponsiveness in the previously activated T cells. Part of the CD4+ T cell population is deleted and the remaining cells are unable to produce IL-2, a state known as anergy (functional inactivation). The CD8+ T cells are less affected and maintain the ability to mediate cytotoxicity in that CD8+ CTLs effectively lyse MHC class II+ target cells in vitro. By analogy, certain MHC class II+ antigen-presenting cells (APC) were shown to be depleted in vivo by a mechanism involving CD8+ T cells and the lytic protein perforin. In a later study, we demonstrated that functional anergy also could be induced in the CD8+ CTLs in a dose-dependent manner. Surprisingly, there seemed to be a difference in the way different cytokines were regulated. Repeated injections of SEA induced the production of large amounts of the 'suppressive' cytokine IL-10 and neutralization of IL-10 in vivo restored IFN-g, TNF, and IL-4 but not IL-2 production. The molecular basis for the perturbed IL-2 synthesis in anergized CD4+ T cells was shown to include the defective expression and regulation of the important transcription factor AP-1. Collectively, these data suggest that multiple immunoregulatory mechanisms cooperate to downregulate and control T cell activity in vivo.

Details

Authors
  • Anette Sundstedt
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Basic Medicine

Keywords

  • transplantation, T cell/superantigen/anergy/interleukin-2/transcription factor/cytotoxicity, serology, Immunology, Immunologi, serologi
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
  • [unknown], [unknown], Supervisor, External person
Award date1998 Apr 25
Publisher
  • Department of Cell and Molecular Biology, Lund University
Print ISBNs91-628-2900-9
Publication statusPublished - 1998
Publication categoryResearch

Bibliographic note

Defence details Date: 1998-04-25 Time: 09:15 Place: Föreläsningssalen Wallenberglaboratoriet, Sölvegatan 33, Lund External reviewer(s) Name: Schwartz, Ronald H. Title: Professor Affiliation: National Institutes of Health, Bethesda, MD ---