Primary and secondary CD8+ T cell responses to pulmonary fungal infection.

The objective of this thesis was to define the role of CD8+ T cells in the pulmonary immune response to the fungal pathogen, Cryptococcus neoformans. In humans, C. neoformans infection is common, but severe disease primarily affects individuals with compromised CD4+ T cell function. Using a established mouse model of pulmonary C. neoformans infection, we studied CD8 + T cell responses to C. neoformans in immunocompetent (CD4+ T cell sufficient) and CD4+ T cell deficient hosts. In immunocompetent mice, CD8+ T cells proliferated in secondary lymphoid tissues, but did not become activated, or acquire effector function until reaching the site of primary infection, where CD8+ T cells in the lungs produced the macrophage activating cytokine IFNgamma. When re-stimulated with a variety of C. neoformans antigens, CD4+ and CD8+ T cells from secondary lymphoid tissues of infected mice proliferated whereas lung T cell produced effector cytokines. These results demonstrated compartmentalized function of CD8 + T cells during pulmonary C. neoformans infection. In many circumstances, CD4+ T cell deficiency results in an impaired CD8+ T cell response. The CD8+ T cell response to C. neoformans was not dependent on CD4 + T cells, and instead CD4+ T cell deficiency resulted in an exaggerated CD8+ T cell response. CD8+ T cells became activated, trafficked to the lungs, and produced IFNgamma in the absence of CD4+ T cells. During CD4+ T cell deficiency, CD8+ T cells provided a level of protection against C. neoformans, promoting monocyte/macrophage recruitment to the lungs, and limiting intracellular infection of macrophages. However, CD8+ T cells alone were not sufficient for resolution of C. neoformans infection. Immunocompetent mice which had resolved primary C. neoformans infection controlled a secondary fungal challenge more rapidly, even in the presence of low-level persistent primary infection. The secondary immune response was characterized by: (1) higher frequencies of IFNgamma production by CD8+ T cells; (2) higher numbers of responding CD8+ T cells; (3) faster resolution of microbial infection; (4) faster resolution of pulmonary inflammation. Cumulatively, these results demonstrate that CD8+ T cells play a complementary role to CD4+ T cells in protective cell-mediated immunity to C. neoformans. During CD4+ T cell deficiency, however, CD8+ T cells play a critical role in limiting pulmonary C. neoformans infection.PhDBiological SciencesHealth and Environmental SciencesImmunologyMedicineMicrobiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124871/2/3163872.pd