HSPs drive dichotomous T-cell immune responses via DNA methylome remodelling in antigen presenting cells

Immune responses primed by endogenous heat shock proteins, specifically gp96, can be varied, and mechanisms controlling these responses have not been defined. Immunization with low doses of gp96 primes T helper type 1 (Th1) immune responses, whereas high-dose immunization primes responses characteri...

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Published inNature communications Vol. 8; no. 1; p. 15648
Main Authors Kinner-Bibeau, Lauren B., Sedlacek, Abigail L., Messmer, Michelle N., Watkins, Simon C., Binder, Robert J.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 31.05.2017
Nature Publishing Group
Nature Portfolio
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Summary:Immune responses primed by endogenous heat shock proteins, specifically gp96, can be varied, and mechanisms controlling these responses have not been defined. Immunization with low doses of gp96 primes T helper type 1 (Th1) immune responses, whereas high-dose immunization primes responses characterized by regulatory T (Treg) cells and immunosuppression. Here we show gp96 preferentially engages conventional and plasmacytoid dendritic cells (pDCs) under low and high doses, respectively, through CD91. Global DNMT-dependent epigenetic modifications lead to changes in protein expression within these antigen-presenting cells. Specifically, pDCs upregulate neuropilin-1 to enable the long term interactions of pDCs with Treg cells, thereby enhancing suppression of Th1 anti-tumour immunity. Our study defines a CD91-dependent mechanism through which gp96 controls dichotomous immune responses relevant to the therapy of cancer and autoimmunity. Low dose of the heat shock protein gp96 can drive effector T-cell responses, yet high-dose gp96 is immunosuppressive by expanding the regulatory T-cell population. Here the authors explain this dichotomy by showing that high-dose gp96 can drive plasmacytoid dendritic cell expression of neuropilin-1, thus functionally supporting interaction with Treg cells.
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ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms15648