Disease-associated dendritic cells respond to disease-specific antigens through the common heat shock protein receptor.
The most abundant intracellular proteins, heat shock proteins (HSPs), serve as molecular chaperones for regulatory and maturation pathways. Diverse families of HSPs have been shown to bind antigenic peptides and to play major roles in innate and adaptive immune responses through the common HSP receptor, CD91. HIV-1+ patients with Kaposi sarcoma (KS) were matched for CD4 count and HIV-1 RNA viral load to HIV-1+ patients without Kaposi sarcoma (and negative for Kaposisarcoma-associated herpesvirus). We then investigated the pathways used by tumor lysates, viral lysates, and viral particles in their activation. In particular, we observed immune responses after HSP depletion using antitumor antibiotics and blockade of the common HSP receptor, CD91. Despite the impaired functional capacity of dendritic cells (DCs) derived from patients with KS, DCs retain the ability to prime the adaptive arm of the immune system through the common HSP receptor, leading to phenotypic activation and stimulation of tetramer-positive CD8+ cytotoxic T cells. We also show that interferon-producing plasmacytoid DCs are selectively depleted in KS-positive compared with matched KS-negative HIV-1-infected patients. Functionally impaired DCs can effectively cross-present immune responses through the common HSP receptor. These results have important implications for the etiopathogenesis of KS and for the development and design of any compounds, including vaccines, derived from cellular lysates.
Stebbing
Justin
J
Department of Immunology, Chelsea and Westminster Hospital, 369 Fulham Rd, London SW10 9NH, United Kingdom. j.stebbing@imperial.ac.uk
Gazzard
Brian
B
Portsmouth
Simon
S
Gotch
Frances
F
Kim
Louise
L
Bower
Mark
M
Mandalia
Sundhiya
S
Binder
Robert
R
Srivastava
Pramod
P
Patterson
Steve
S
D000163:Acquired Immunodeficiency Syndrome / Q000150:complications / Q000276:immunology*; D000941:Antigens / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018869:Heat-Shock Response / Q000276:immunology; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D009000:Monocytes / Q000166:cytology; D012514:Sarcoma, Kaposi / Q000276:immunology* / Q000821:virology; D012878:Skin Neoplasms / Q000276:immunology* / Q000821:virology; D014771:Virion / Q000276:immunology
D000941:Antigens; D015703:Antigens, CD; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1