Calnexin induces expansion of antigen-specific CD4+ T cells that confer immunity to fungal ascomycetes via conserved epitopes

Marcel Wüthrich, Tristan T. Brandhorst, Thomas D. Sullivan, Hanna Filutowicz, Alana Sterkel, Douglas Stewart, Mengyi Li, Tassanee Lerksuthirat, Vanessa Lebert, Zu Ting Shen, Gary Ostroff, George S. Deepe, Chiung Yu Hung, Garry Cole, Jennifer A. Walter, Marc K. Jenkins, Bruce Klein

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Fungal infections remain a threat due to the lack of broad-spectrum fungal vaccines and protective antigens. Recent studies showed that attenuated Blastomyces dermatitidis confers protection via T cell recognition of an unknown but conserved antigen. Using transgenic CD4+ T cells recognizing this antigen, we identify an amino acid determinant within the chaperone calnexin that is conserved across diverse fungal ascomycetes. Calnexin, typically an ER protein, also localizes to the surface of yeast, hyphae, and spores. T cell epitope mapping unveiled a 13-residue sequence conserved across Ascomycota. Infection with divergent ascomycetes, including dimorphic fungi, opportunistic molds, and the agent causing white nose syndrome in bats, induces expansion of calnexin-specific CD4+ T cells. Vaccine delivery of calnexin in glucan particles induces fungal antigen-specific CD4+ T cell expansion and resistance to lethal challenge with multiple fungal pathogens. Thus, the immunogenicity and conservation of calnexin make this fungal protein a promising vaccine target.

Original languageEnglish (US)
Pages (from-to)452-465
Number of pages14
JournalCell Host and Microbe
Volume17
Issue number4
DOIs
StatePublished - Apr 8 2015

Bibliographical note

Funding Information:
This work was supported by NIH grants AI040996 and AI105816 to B.K.; AI093553 to M.W.; AI103760 to M.K.J.; and AI071118 to G.C. and T.L. and by a Royal Golden Jubilee Ph.D. Scholarship Grant (PHD/0092/2553) from Mahidol University, Bangkok, Thailand to T.L. We thank Robert Gordon for help with illustrations; Paul Ahlquist for loaning the gel-free system; the Nett and Huttenlocher labs for helping collect blood samples; Drs. Nancy Keller, David Blehert, and Gordon Brown for providing fungal strains; and Emily Carrow (Advanced BioAduvants), who provided Adjuplex, and M. Suresh, who advised on its use.

Publisher Copyright:
© 2015 Elsevier Inc.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

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