Interleukin-1 Receptor but Not Toll-Like Receptor 2 Is Essential for MyD88-Dependent Th17 Immunity to Coccidioides Infection

Abstract

ABSTRACTInterleukin-17A (IL-17A)-producing CD4+T helper (Th17) cells have been shown to be essential for defense against pulmonary infection withCoccidioidesspecies. However, we have just begun to identify the required pattern recognition receptors and understand the signal pathways that lead to Th17 cell activation after fungal infection. We previously reported thatCard9−/−mice vaccinated with formalin-killed spherules failed to acquire resistance toCoccidioidesinfection. Here, we report that bothMyD88−/−andCard9−/−mice immunized with a live, attenuated vaccine also fail to acquire protective immunity to this respiratory disease. LikeCard9−/−mice, vaccinatedMyD88−/−mice revealed a significant reduction in numbers of both Th17 and Th1 cells in their lungs afterCoccidioidesinfection. Both Toll-like receptor 2 (TLR2) and IL-1 receptor type 1 (IL-1r1) upstream of MyD88 have been implicated in Th17 cell differentiation. Surprisingly, vaccinatedTLR2−/−and wild-type (WT) mice showed similar outcomes after pulmonary infection withCoccidioides, while vaccinatedIL-1r1−/−mice revealed a significant reduction in the number of Th17 cells in their infected lungs compared to WT mice. Thus, activation of both IL-1r1/MyD88- and Card9-mediated Th17 immunity is essential for protection againstCoccidioidesinfection. Our data also reveal that the numbers of Th17 cells were reduced inIL-1r1−/−mice to a lesser extent than inMyD88−/−mice, raising the possibility that other TLRs are involved in MyD88-dependent Th17 immunity to coccidioidomycosis. An antimicrobial action of Th17 cells is to promote early recruitment of neutrophils to infection sites. Our data revealed that neutrophils are required for vaccine immunity to this respiratory disease.