Differential and cooperative effects of IL-25 and IL-33 on T helper cells contribute to cryptococcal virulence and brain infection

Cryptococcal disease pathogenesis is associated with the induction of type 2 immune response which is largely mediated by adaptive T helper cells. Recently, epithelial cell-derived IL-33 and IL-25 are recognized as key mediators in driving pathogenic type 2 inflammation during C. neoformans infection. Although IL-25 and IL-33 exhibit a combinatorial and closely related function, the differential effect of these cytokines in the regulation of host immune response against C. neoformans infection is still elusive. We observed a predominantly increase of IL-25/IL-33 responsive Th cells within the lung after infection, especially at the chronic infection phase. The ex vivo stimulation of cryptococcal-specific Th cells demonstrated combinatorial effect of IL-25 and IL-33 in promoting the production of type 2 cytokines. A comparative transcriptomic analysis revealed coordinatel effects of these cytokines in promoting activation, survival, and homeostasis of adaptive Th cells during C. neoformans infection. The expression of type 2 cytokines and chemokine was absent in Th cells of Il17rb-/- mice, indicating the requirement of IL-25-mediated Th2-type immune responses during C. neoformans infection. Further analysis of the degree of virulence indicated a positive correlation between the frequency of IL-17RB/ST2-expressing Th cells and cryptococcal brain dissemination in vivo. Comparative gene expression profiling analysis of RNA-seq data of IL-25 and IL-33 treated effector CD4+ T helper cell isolated from the lung of BALB/c and Il17rb-/- m