Role of Common γ-Chain Cytokines in Lung Interleukin-22 Regulation after Acute Exposure to Aspergillus fumigatus

Abstract

Humans are constantly exposed to the opportunistic mold <i>Aspergillus fumigatus</i>, and disease caused by this pathogen is often determined by the magnitude of local and systemic immune responses. We have previously shown a protective role for interleukin-22 (IL-22) after acute <i>A. fumigatus</i> exposure. Here, employing IL-22^Cre R26R^eYFP reporter mice, we identified iNKT cells, γδ T cells, and type 3 innate lymphoid cells (ILC3s) as lung cell sources of IL-22 in response to acute <i>A. fumigatus</i> exposure. As these cells often utilize common γ-chain cytokines for their development or maintenance, we determined the role of IL-7, IL-21, and IL-15 in lung IL-22 induction and <i>A. fumigatus</i> lung clearance. We observed that IL-7, IL-21, and IL-15 were essential for, partially required for, or negatively regulated the production of IL-22, respectively. Deficiency in IL-7 and IL-21, but not IL-15R, resulted in impaired fungal clearance. Surprisingly, however, the absence of IL-7, IL-21, or IL-15R signaling had no effect on neutrophil recruitment. The levels of IL-1α, an essential anti-<i>A. fumigatus</i> proinflammatory cytokine, were increased in the absence of IL-7 and IL-15R but decreased in the absence of IL-21. IL-7 was responsible for maintaining lung iNKT cells and γδ T cells, whereas IL-21 was responsible for maintaining lung iNKT cells and ILC3s. In contrast, IL-15R deficiency had no effect on the absolute numbers of any IL-22 cell source, rather resulting in enhanced per cell production of IL-22 by iNKT cells and γδ T cells. Collectively, these results provide insight into how the IL-22 response in the lung is shaped after acute <i>A. fumigatus</i> exposure.