S7.4a Vaccine-inducing lung resident CD4 + memory T cells are protective against Cryptococcus gattii infections

Abstract

S7.4 Pathogenesis and host defense, September 23, 2022, 10:30 AM - 12:00 PM Cryptococccus gattii is a highly virulent fungal pathogen that can cause cryptococcosis in previously healthy individuals. It is not fully understood how innate and acquired immune responses cooperatively suppress C. gattii infection. Hitherto, we have reported the following findings, (1) Specific environment for exposure of dectin-1 and dectin-2 ligands in cryptococcal cells (PLOS ONE 2019, PMID 31398236), (2) CD11b-mediated immune recognition for C. gattii and capsule dependent immune evasion from CD11b recognition (Eur J Immunol 2021, PMID 33728652), (3) Dendritic cells (DCs)-based vaccine induced lung resident memory Th17 cells and ameliorates C. gattii infection (Mucosal Immunol 2018, PMID 30279512), and (4) Neutrophil and opsonization can mediate fungicidal activity for cryptococcal cells (Med Mycol 2019, PMID 30668754). Based on these findings, we have inferred that induction of lung resident memory T cells (lung TRM) and TRM-driven myeloid cells including granulocytes is necessary for controlling this infection. Currently, we are developing new intranasal (IN) vaccines using highly immunogenic whole cell antigens and characterizing protective lung TRM induced by the vaccines. Just as with component vaccines, whole cell vaccines are also featured for cryptococcal infection because these are highly cross-reactive and protective against each serotype (Biol Pharm Bull 2020, PMID 32009111). We developed two IN vaccines using whole cell antigen and adjuvant. Both vaccines induced IL-5-producing lung TRM and significantly reduced fungal burden in lungs and improved survival rates of mice following C. gattii infection, while not protective against C. neoformans infection. Although immune suppressive agent FTY720 can eliminate most circulating T cells and sustain tissue-resident subset, IN vaccines induced Th2-related immune response including eosinophils and IFN-γ independent granuloma, and reduced the fungal burden in lungs after the infection in the presence of FTY720. Vaccine-mediated protection was completely lost in the Rag-1 knockout mice deficient in T- and B-cells, while the fungal burden was reduced in the Rag-1 knockout mice after receiving the immunized CD4 + T cells in the adoptive transfer experiments. These results suggest that Th2-related lung TRM induced by IN vaccines are also protective against C. gattii infection as well as Th17-related counterparts induced by DC vaccine.