title: CD4+ T cells mediate the protective effect of the recombinant Asp f3-based anti-aspergillosis vaccine.
abstract: The mortality and morbidity caused by invasive aspergillosis present a major obstacle to the successful treatment of blood cancers with hematopoietic cell transplants. Patients who receive hematopoietic cell transplants are usually immunosuppressed for extended periods, and infection with the ubiquitous mold Aspergillus fumigatus is responsible for most cases of aspergillosis. Previously, we demonstrated that vaccination with recombinant forms of the A. fumigatus protein Asp f3 protected cortisone acetate-immunosuppressed mice from experimentally induced pulmonary aspergillosis. Here, we investigated the vaccine's protective mechanism and evaluated in particular the roles of antibodies and T cells. After vaccination, Asp f3-specific preinfection IgG titers did not significantly differ between surviving and nonsurviving mice, and passive transfer of anti-Asp f3 antibodies did not protect immunosuppressed recipients from aspergillosis. We experimentally confirmed Asp f3's predicted peroxisomal localization in A. fumigatus hyphae. We found that fungal Asp f3 is inaccessible to antibodies, unless both cell walls and membranes have been permeabilized. Antibody-induced depletion of CD4+ T cells reduced the survival of recombinant Asp f3 (rAsp f3)-vaccinated mice to nonimmune levels, and transplantation of purified CD4+ T cells from rAsp f3-vaccinated mice into nonimmunized recipients transferred antifungal protection. In addition, residues 60 to 79 and 75 to 94 of Asp f3 contain epitopes that induce proliferation of T cells from vaccinated survivors. Vaccine-primed CD4+ T cells are not expected to clear the fungal pathogen directly; however, they may locally activate immunosuppressed phagocytes that elicit the antifungal effect.
authors.affiliation: City of Hope, Beckman Research Institute, Department of Immunology, 1500 East Duarte Road, Duarte, CA 91010-3000, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Diaz-Arevalo
authors.forename: Karine
authors.initials: K
authors.lastname: Bagramyan
authors.forename: Teresa B
authors.initials: TB
authors.lastname: Hong
authors.forename: James I
authors.initials: JI
authors.lastname: Ito
authors.forename: Markus
authors.initials: M
authors.lastname: Kalkum
mesh_terms: D000485:Allergens; D000818:Animals; D000908:Antibodies, Fungal / Q000276:immunology; D052179:Antigens, Plant / Q000276:immunology*; D001228:Aspergillosis / Q000276:immunology* / Q000517:prevention & control; D001232:Aspergillus fumigatus / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005657:Fungal Vaccines / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D011817:Rabbits; D014614:Vaccines, Synthetic / Q000276:immunology
chemical_list: D000485:Allergens; D000908:Antibodies, Fungal; D052179:Antigens, Plant; C115315:Asp f 3 allergen; D005657:Fungal Vaccines; D014614:Vaccines, Synthetic