Activation of thymic T cells by MHC alloantigen can require syngeneic activated CD4 T cells and B cells as APC
Strutt, Tara Marlene
An immunological mechanism to account for the regulation of peripheral self-reactive T cells, which escape central tolerance in the thymus, during the primary activation of naïve, foreign antigen-specific T cells remains to be established. Contemporary models of primary T cell activation that attempt to describe how this occurs differ significantly in the cellular interactions necessary for naïve CD4+ T helper cell activation. It is generally accepted that most CD8+ T cells are dependent upon CD4+ T helper cells for their activation. The Infectious Non-Self and Danger Models of CD4+ T cell activation propose that interaction of a naïve T cell with an appropriately armed dendritic cell is sufficient, whereas the Two-step, Two-signal Model proposes additional cellular interactions are necessary. The major goal of this thesis was to establish and utilize an in vitro experimental system that would allow one to begin to delineate which model most validly describes the cellular interactions required for generation of primary immune responses from naïve T cells. Employing a population of naïve T cells uncontaminated with any partially or fully activated cells is essential for such a study.The results presented in this thesis show, that when thymocytes are employed as a source of responding naïve T cells, cellular interactions, in addition to interaction with bone marrow derived dendritic cells, are required for the activation of naïve thymic T cells. The primary activation of thymic T cells to generate CD4+ IL-2 producing cells, and CD8+ IFN-g producing cells and cytotoxic T cells upon stimulation with splenic allogeneic stimulator cells is critically dependent upon the presence of a syngeneic population of radiation resistant, CD4+ T cells found in the spleen of normal mice. Additionally, when such cells are present as a source of “help” for thymocytes, allogeneic bone marrow derived dendritic cells fail to stimulate the generation of optimal cytotoxic and cytokine responses from naïve thymic T cells. However, they do stimulate thymocytes to cycle and up regulate the ligand for the costimulatory molecule CD40, CD40L.The results presented within also show that the optimal activation of naïve thymic T cells to generate CD4+ IL-2 producing cells, and CD8+ IFN-g producing cells and cytotoxic T cells, requires the presence of allo-MHC bearing Ig+ B220+ B cells. The removal of B220+ cells by magnetic cell sorting from the allogeneic spleen reveals that the generation of CD8+ cytotoxic T cells and IFN-g producing cells from thymocytes is markedly reduced compared to unsorted allogeneic spleen cells. However, IL-2 and IL-4 cytokine producing cells are still detectable. Potential reasons for the generation of the latter cytokine producing cells are discussed. The results presented in this thesis have revealed insights into the cellular interactions involved in the activation of naïve thymic T cells.
DegreeDoctor of Philosophy (Ph.D.)
DepartmentMicrobiology and Immunology
ProgramMicrobiology and Immunology
SupervisorBretscher, Peter A.
CommitteeHayGlass, Kent T.; Hayes, Sidney; Havele, Calliopi; Gordon, John R.; Qualtiere, Louis
Copyright DateApril 2005