探討低MHC class II表現量和Galectin-3在清除組織胞漿菌感染中扮演的角色

Abstract

Histoplasma capsulatum (Hc) is opportunistic dimorphic fungal pathogen. It grows as mycelium in the soil in nature and transforms into yeast form upon inhalation of its microconidia or hyphal fragments into lungs, residing within alveolar macrophages as intracellular pathogen. Clearance of Hc infection needs the development of Th1 immune response and IFN-γ production by CD4 T cells. Mice depleted IFN-γ or MHC class II gene knockout mice fail to clear fungus and succumb to sublethal dose of Hc infection. B cell has been proved to play a mild role in Hc primary and secondary infection, although it can be activated by IFN-γ and underwent isotype switch, producing immunoglobulin G after infection. There is no report that addressed the question that whether the existence of B cells reduces the availability of IFN-γ. I used ENU-mutagenized mice P-235, which are characterized by low MHC class II expression and fewer B cell counts, to investigate the balance between IFN-γ production by CD4 T cells and IFN-γ comsumption by B cells. My results showed that despite of fewer IFN-γ-producing T cells, the fungal clearances in P-235 mice are as effecicient as in WT mice after primary and secondary Hc infection, since the absence of B cells resulted in higher IFN-γ levels in different tissues of P-235 mice than WT mice. It indicated that B cells consumed IFN-γ produced by T cells and affected host resistence to Hc infection. Moreover, this effect is uncovered only in P-235 mice, because IFN-γ produced by activated T cells in WT mice is enough to clear Hc infection. It has been reported that galectin-3 regulated proinflammatory responses and Th1 immune response in Toxplasma gondii, Rhodococcus equi, and Streptococcus pneumonia infection. Moreover, recent research indicated that IL-17-producing cells contributed to inflammation in Mycobacterium tuberculosis and Candida albicans infection. It remains to be elucidated that whether the regulation of immune responses by galectin-3 is through IL-17 production, and whether the bias of immune responses in galectin-3 knockout mice affects fungal clearance after Hc infection. Using the mouse model of systemic histoplasmosis characterized by a strong Th1 response, I demonstrated that the fungal load in galectin-3 knockout mice was lower than in WT mice, and the increased IL-17 production by CD4 T cells and neutrophils in galectin-3 knockout mice contributed to this result. Based on these results, I can investigate how galectin-3 regulates IFN-g and IL-17 productions further.