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

Abstract

The objective of this thesis was to define the role of CD8<super>+</super> T cells in the pulmonary immune response to the fungal pathogen, <italic> Cryptococcus neoformans</italic>. In humans, <italic>C. neoformans</italic> infection is common, but severe disease primarily affects individuals with compromised CD4<super>+</super> T cell function. Using a established mouse model of pulmonary <italic>C. neoformans</italic> infection, we studied CD8<super> +</super> T cell responses to <italic>C. neoformans</italic> in immunocompetent (CD4<super>+</super> T cell sufficient) and CD4<super>+</super> T cell deficient hosts. In immunocompetent mice, CD8<super>+</super> 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<super>+</super> T cells in the lungs produced the macrophage activating cytokine IFNgamma. When re-stimulated with a variety of <italic>C. neoformans</italic> antigens, CD4<super>+</super> and CD8<super>+</super> T cells from secondary lymphoid tissues of infected mice proliferated whereas lung T cell produced effector cytokines. These results demonstrated compartmentalized function of CD8<super> +</super> T cells during pulmonary <italic>C. neoformans</italic> infection. In many circumstances, CD4<super>+</super> T cell deficiency results in an impaired CD8<super>+</super> T cell response. The CD8<super>+</super> T cell response to <italic>C. neoformans</italic> was not dependent on CD4<super> +</super> T cells, and instead CD4<super>+</super> T cell deficiency resulted in an exaggerated CD8<super>+</super> T cell response. CD8<super>+</super> T cells became activated, trafficked to the lungs, and produced IFNgamma in the absence of CD4<super>+</super> T cells. During CD4<super>+</super> T cell deficiency, CD8<super>+</super> T cells provided a level of protection against <italic>C. neoformans</italic>, promoting monocyte/macrophage recruitment to the lungs, and limiting intracellular infection of macrophages. However, CD8<super>+</super> T cells alone were not sufficient for resolution of <italic> C. neoformans</italic> infection. Immunocompetent mice which had resolved primary <italic>C. neoformans </italic> 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<super>+</super> T cells; (2) higher numbers of responding CD8<super>+</super> T cells; (3) faster resolution of microbial infection; (4) faster resolution of pulmonary inflammation. Cumulatively, these results demonstrate that CD8<super>+</super> T cells play a complementary role to CD4<super>+</super> T cells in protective cell-mediated immunity to <italic> C. neoformans</italic>. During CD4<super>+</super> T cell deficiency, however, CD8<super>+</super> T cells play a critical role in limiting pulmonary <italic> C. neoformans</italic> infection.