CCR5-mediated recruitment of NK cells to the kidney is a critical step for host defense to systemic Candida albicans infection

Abstract CCR5 regulates the trafficking of various immune cells to the site of infection. Expression of CCR5 and its ligands were rapidly increased in the kidney after systemic Candida albicans infection and infected CCR5−/− mice showed increased mortality and morbidity, indicating that CCR5 contributes to an effective defense mechanism against systemic C. albicans infection. The susceptibility of CCR5−/− mice to C. ablicans infection was due to their impaired capacity of fungal clearance, which in turn resulted in exacerbated renal inflammation and damage. CCR5-mediated recruitment of NK cells to the kidney in response to C. albicans infection was necessary for the anti-microbial activity of neutrophils, the main fungicidal effector cells. Mechanistically, C. albicans rapidly induced expression of IL-23 and IL-15 by CD11b+CD11c+ dendritic cells (DCs) and Ly6C+ monocytes, respectively. IL-23 and IL-15 in turn augmented the fungicidal activity of neutrophils through GM-CSF production by NK cells. As GM-CSF potentiated production of IL-23 and IL-5 in response to C. albicans, a positive feedback loop formed between NK cells and DCs or Ly6C+ monocytes seemed to function as a central amplification point for host defense. Taken together, our results suggest that CCR5-mediated recruitment of NK cells to the site of fungal replication is a critical step that underlies innate resistance to systemic C. albicans infection.