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Urokinase-Type Plasminogen Activator Is Required for the Generation of a Type 1 Immune Response to Pulmonary Cryptococcus neoformans Infection¹

Margaret R. Gyetko^2,*, Sudha Sud^*, Gwo-Hsiao Chen^*, Jennifer A. Fuller^*, Stephen W. Chensue and Galen B. Toews^*

^* Pulmonary and Critical Care Medicine Division, Departments of Internal Medicine and Pathology, Ann Arbor Veterans Affairs Medical Center and University of Michigan Medical Center, Ann Arbor, MI 48109

Urokinase-type plasminogen activator (uPA)^-/- mice cannot mount protective host defenses during infection with the opportunistic yeast Cryptococcus neoformans (52D). Because effective host defense against C. neoformans requires specific immune responses and the generation of type 1 (T1) cytokines, we determined how the absence of uPA impacts these processes. Wild-type (WT) and uPA^-/- mice were inoculated with C. neoformans. Macrophage antifungal activity was assessed histologically, T lymphocyte responses in vivo and proliferation in vitro were quantified, and cytokine concentrations were determined by ELISA. uPA^-/- macrophages have impaired antimicrobial activity. Regional lymph nodes of infected uPA^-/- mice contained fewer cells than WT, suggesting impaired T cell proliferation in response to the pathogen in vivo. In vitro, uPA^-/- T lymphocytes had impaired proliferative responses to C. neoformans rechallenge compared with WT. Infected WT mice generated T1 cytokines in the lung, characterized by high levels of IFN- and IL-12. uPA^-/- mice had decreased levels of IFN- and IL-12, and increased IL-5, a type 2 cytokine. In the absence of uPA, the cytokine profile of regional lymph nodes shifted from a T1 pattern characterized by IFN- and IL-2 to a weak, nonpolarized response. We conclude that in the absence of uPA, lymphocyte proliferative responses are diminished, and mice fail to generate protective T1 cytokines, resulting in impaired antimicrobial activity. This study provides novel evidence that uPA is a critical modulator of immune responses and of immune cell effector functions in vivo.

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