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

doi:10.1016/j.chom.2015.02.009

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

Microbiology

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	452-465
Number of pages	14
Journal	Cell Host and Microbe
Volume	17
Issue number	4
DOIs	https://doi.org/10.1016/j.chom.2015.02.009
State	Published - 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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Wüthrich, M., Brandhorst, T. T., Sullivan, T. D., Filutowicz, H., Sterkel, A., Stewart, D., Li, M., Lerksuthirat, T., Lebert, V., Shen, Z. T., Ostroff, G., Deepe, G. S., Hung, C. Y., Cole, G., Walter, J. A., Jenkins, M. K., & Klein, B. (2015). Calnexin induces expansion of antigen-specific CD4⁺ T cells that confer immunity to fungal ascomycetes via conserved epitopes. Cell Host and Microbe, 17(4), 452-465. https://doi.org/10.1016/j.chom.2015.02.009

Calnexin induces expansion of antigen-specific CD4⁺ T cells that confer immunity to fungal ascomycetes via conserved epitopes. / Wüthrich, Marcel; Brandhorst, Tristan T.; Sullivan, Thomas D.; Filutowicz, Hanna; Sterkel, Alana; Stewart, Douglas; Li, Mengyi; Lerksuthirat, Tassanee; Lebert, Vanessa; Shen, Zu Ting; Ostroff, Gary; Deepe, George S.; Hung, Chiung Yu; Cole, Garry; Walter, Jennifer A.; Jenkins, Marc K.; Klein, Bruce.

In: Cell Host and Microbe, Vol. 17, No. 4, 08.04.2015, p. 452-465.

Research output: Contribution to journal › Article › peer-review

Wüthrich, M, Brandhorst, TT, Sullivan, TD, Filutowicz, H, Sterkel, A, Stewart, D, Li, M, Lerksuthirat, T, Lebert, V, Shen, ZT, Ostroff, G, Deepe, GS, Hung, CY, Cole, G, Walter, JA, Jenkins, MK & Klein, B 2015, 'Calnexin induces expansion of antigen-specific CD4⁺ T cells that confer immunity to fungal ascomycetes via conserved epitopes', Cell Host and Microbe, vol. 17, no. 4, pp. 452-465. https://doi.org/10.1016/j.chom.2015.02.009

Wüthrich, Marcel ; Brandhorst, Tristan T. ; Sullivan, Thomas D. ; Filutowicz, Hanna ; Sterkel, Alana ; Stewart, Douglas ; Li, Mengyi ; Lerksuthirat, Tassanee ; Lebert, Vanessa ; Shen, Zu Ting ; Ostroff, Gary ; Deepe, George S. ; Hung, Chiung Yu ; Cole, Garry ; Walter, Jennifer A. ; Jenkins, Marc K. ; Klein, Bruce. / Calnexin induces expansion of antigen-specific CD4⁺ T cells that confer immunity to fungal ascomycetes via conserved epitopes. In: Cell Host and Microbe. 2015 ; Vol. 17, No. 4. pp. 452-465.

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

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.",

author = "Marcel W{\"u}thrich and Brandhorst, {Tristan T.} and Sullivan, {Thomas D.} and Hanna Filutowicz and Alana Sterkel and Douglas Stewart and Mengyi Li and Tassanee Lerksuthirat and Vanessa Lebert and Shen, {Zu Ting} and Gary Ostroff and Deepe, {George S.} and Hung, {Chiung Yu} and Garry Cole and Walter, {Jennifer A.} and Jenkins, {Marc K.} and Bruce Klein",

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AU - Sterkel, Alana

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AU - Li, Mengyi

AU - Lerksuthirat, Tassanee

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N2 - 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.

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