Cytokine regulation in pulmonary chronic fungal infection.

Abstract

<italic>C. neoformans</italic> is a pulmonary fungal pathogen that requires the development of T1 immunity to clear the infection. The development of T2 responses results in susceptibility and is characterized by the recruitment of eosinophils into the lungs, high serum IgE levels, and production of T2 cytokines such as IL-4, IL-5, and IL-13. The events that characterize the early phases of the T2 responses to <italic>C. neoformans</italic> remain unknown. The goal of this thesis was to determine the role of IFN-gamma, IL-4, IL-10, and IL-5 in susceptibility to <italic>C. neoformans</italic> using C57BL/6 background mice with a disruption in the gene that encodes for these cytokines (knockout mice). This thesis explored the hypotheses that susceptibility to <italic>C. neoformans</italic> results from the up-regulation of T2 cytokine(s) or the down-regulation of T1 cytokine(s), or a combination of both. The approach used throughout these studies was to intratracheally inoculate mice with 10<super>4</super> <italic>C. neoformans</italic> organisms and analyze the immune response in the lungs and lung-associated lymph nodes at weeks 1, 2, and 3 after infection (by measuring cytokine levels in culture supernatants and analyzing cellular recruitment in vivo). Results indicated that the development of a weak T1 signal (IFN-gamma) combined with the production or upregulation of T2 cytokines (IL-4, IL-5, and IL-13) promoted the development of a chronic pulmonary cryptococcus infection. This thesis demonstrated that in susceptible C57BL/6 mice, (a) IFN-gamma plays a protective role by inducing a chronic infection (fungistasis), (b) IL-4 is a key T2 differentiation factor that induces T2 responses in the lungs and systemically, (c) IL-10 promotes the development of T2 responses in the lungs, and (d) IL-5 is required for pulmonary eosinophilia and may play a role in modulating T2 immunity. Additionally, the production of IFN-gamma is independent of the production of IL-4, IL-5, and IL-10; however, IFN-gamma negatively regulates the production of IL-4, IL-5, and IL-13 in the lungs. This thesis demonstrated some of the regulatory roles that T1 and T2 cytokines play in susceptibility to <italic> C. neoformans</italic>, provided an immunologic foundation for future studies of an allergic bronchopulmonary fungal infection, and contributed to a general understanding of the development and regulation of immunity in the lungs.