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

• Published in: Nature 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
• Language: English
• Published: London Nature Publishing Group UK 31.05.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 14/19; 14/35; 38/39; 38/77; 631/250/21/1293; 631/250/2502/2170; 631/250/2504/133/1412; 631/250/580; 64/60; 82/29; 82/83; Animals; Antigens; Bone Marrow Cells - cytology; Cancer; Cell Adhesion; Dendritic cells; Dendritic Cells - immunology; DNA - chemistry; DNA Methylation; Endocytosis; Epigenetics; Female; Heat shock proteins; Heat-Shock Proteins - immunology; Humanities and Social Sciences; Immunity, Cellular; Immunology; Male; Melanoma, Experimental; Membrane Glycoproteins - immunology; Mice; Mice, Inbred C57BL; Microscopy, Confocal; multidisciplinary; Neoplasm Transplantation; Neuropilin-1 - immunology; Peptides; Phenotype; Protein Binding; Science; Science (multidisciplinary); Signal Transduction; T-Lymphocytes, Regulatory - immunology; Tumors; United States > US; Pennsylvania
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms15648

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.