| The adaptive immune response against intracellular pathogens is largely mediated by CD8+ T lymphocytes. The clonal expansion and expression of cytolytic and immune stimulatory proteins by CD8+ T cells is responsible for their protective immune function. Prior to exhibiting effector activity, CD8+ T cells exist in a naive state and require three stimulatory signals for their optimal activation including the recognition of antigen, co-stimulator ligand engagement, and the presence of pro-inflammatory cytokines. When these activation requirements are met, CD8+ T cells undergo a well described series of events including clonal expansion, cellular contraction, memory generation, and memory maintenance. The memory CD8+ T cell population generated can survive for the life-time of the host, and provides more rapid and robust protection upon reinfection then their naive precursors. While some factors that induce this sequence of events have been identified, the role of co-stimulation remains relatively undefined. This is due to the large number of co-stimulator receptors expressed by CD8+ T cells that may be ligated individually and/or in combination, to instruct the development of specific effector and memory CD8 + T cell phenotypes.;Using a bead-based ligand presentation system, I investigated the role of co-stimulation in directing naive CD8+ T cell activation, and the generation of T cell populations with distinct effector and memory fates. I identified ICAM-1 as the stimulatory molecule best able to induce naive CD8+ T cell proliferation and expression of the effector molecule granzyme B, while co-stimulation through CD28 was required to induce IFN-gamma. When provided in combination however, B7.1 and ICAM-1 co-stimulation generated CD8+ T cells which were highly cytolytic and expressed high amounts of IFN-gamma. These cells also exhibited enhanced survival once activated, with sustained expression of anti-apoptotic proteins and secretion of high amounts of IL-2, resulting in these cells exhibiting a terminal effector phenotype. While other co-stimulator combinations also enhanced CD8+ T cell survival to some degree, their ability to sustain high expression of IL-2 was limited. This translated into less potent effector responses and preferential memory precursor development based on transcription factor expression. |
