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

Lauren B. Kinner-Bibeau, Abigail L. Sedlacek, Michelle N. Messmer, Simon C. Watkins and Robert J. Binder ()
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Lauren B. Kinner-Bibeau: University of Pittsburgh
Abigail L. Sedlacek: University of Pittsburgh
Michelle N. Messmer: Roswell Park Cancer Institute
Simon C. Watkins: University of Pittsburgh
Robert J. Binder: University of Pittsburgh

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15648

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