Immunosuppressive effects of CCL17 on pulmonary antifungal responses during pulmonary invasive Aspergillosis

Aspergillus fumigatus-sensitized CCR4-deficient (CCR4(-/-)) mice exhibit an accelerated clearance of conidia during fungal asthma. In the present study, we examined the roles of CCL17 and CCL22, two CCR4 ligands, during pulmonary invasive aspergillosis in neutropenic mice. Kaplan-Meier survival curve analysis revealed that wild-type C57BL/6 (CCR4(+/+)) mice were significantly protected from the lethal effects of Aspergillus compared with their wild-type controls following systemic neutralization with anti-CCL17 but not anti-CCL22 antibodies. Systemic neutralization of CCL17 significantly increased whole-lung CCL2 levels. Mouse survival and histological analysis revealed that the receptor mediating the deleterious effects of CCL17 was CCR4 since mice genetically deficit in CCR4 (CCR4-/-) did not develop invasive aspergillosis. Enzyme-linked immunosorbent assay analysis of whole-lung samples at day 2 after conidial challenge in neutrophil-depleted CCR4(-/-) and CCR4(+/+) mice revealed that whole-lung IL-12 levels were significantly increased in the CCR4-/- group compared with the wild-type group. Also at day 2 after conidial challenge, significantly greater numbers of CD11c(+) F4/80(+) and CD11c(+)/CD86(+) but fewer CD3/NK1.1(+) cells were present in the lungs of CCR4-/- mice compared with their wild-type counterparts. Thus, CCL17-CCR4 interactions dramatically impair the pulmonary antifungal response against A. fumigatus in neutropenic mice.