The role of pulmonary innate and adaptive immune responses to helminth infection
Immunity to nematode infections requires a host T helper 2 (Th2) response promoted by epithelial cell driven IL-33 induction of cytokine secretion of Interleukin (IL)-4, 5 and 13 by a range of immune cells including innate lymphoid cells type 2 (ILC2s) and CD4+ T cells. This induces effector responses such as goblet cell mucus secretion and mast cell activation driving disease resolution. Finding candidate molecules and discrete cell populations that enhance these responses would provide new targets for treating infection via specific host immune-modulation and would contribute to the development of effective vaccines against nematode infections. In this study we addressed how novel components of host adaptive and innate immunity can contribute to pulmonary control of Nippostrongylus brasiliensis infections. Murine reinfection studies with the parasitic nematode N. brasiliensis have shown development of a Th2 CD4+ T cell responses in the lung to be essential for immunity to secondary N. brasiliensis infection. To test if T cell recruitment from secondary lymphoid tissue contributed to this immunity, we used the drug Fingolimod (FTY720) to block T cell egress from lymph nodes (LN) to peripheral tissue. T cell egress from the LN was required for resolution of a primary infection but not for secondary infection. The presence of tissue-resident IL-4Rα responsive CD4+ T cells in the lung was sufficient for protective immunity to N. brasiliensis reinfection. These results demonstrated that effective CD4+ T cell Th2 immunity can be generated at peripheral sites by pre-existing T cell populations, independently of T cell recruitment from secondary lymphoid organs (SLO). Additionally, we identify that the pulmonary epithelial cell-secreted collectin, surfactant protein D (SP-D), is an important component of host immunity to N. brasiliensis infection. We demonstrate here that SP-D production is induced following N. brasiliensis infection in a Th2 dependent manner, it bound preferentially to lung stage L4 parasites and enhanced macrophage and ILC2 protective responses essential for controlling infection. vi Taken together the data presented in this thesis provides two new important insights into pulmonary host immunity to parasitic helminth infections.
Networked Digital Library of Theses and Dissertations
Department of Clinical Laboratory Sciences