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Prepublished online as a Blood First Edition Paper on May 15, 2003; DOI 10.1182/blood-2003-03-0891.
Submitted March 24, 2003
Accepted May 1, 2003
Disease associated dendritic cells respond to disease-specific antigens through the common heat shock protein receptor
Justin Stebbing*, Brian Gazzard, Simon Portsmouth, Frances Gotch, Louise Kim, Mark Bower, Sundhiya Mandalia, Robert Binder, Pramod Srivastava, and Steve Patterson
Department of Immunology, Division of Investigative Science, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, The Chelsea and Westminster Hospital, 369 Fulham Road, London, United Kingdom
Center for Immunotherapy for Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT, USA
* Corresponding author; email: j.stebbing{at}ic.ac.uk.
Background: 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 play major roles in both innate and adaptive immune responses via the common heat shock protein receptor, CD91. We investigated the potential role of this pathway in HIV-1 seropositive individuals with and without Kaposi's sarcoma (KS). Methods: HIV-1 positive individuals with KS were matched for CD4 count and HIV-1 RNA viral load to HIV-1 positive patients without Kaposi's sarcoma (and negative for Kaposi's sarcoma-associated herpesvirus). Dendritic cell populations and subsets were separated, quantified and their potentials for stimulating naive T cells were compared. We then investigated the pathways utilised by tumour lysates, viral lysates and viral particles in their activation. In particular, we observed immune responses following heat shock protein depletion using anti-tumour antibiotics and blockade of the common heat shock protein receptor, CD91. Findings: Despite an impaired functional capacity of dendritic cells derived from individuals with KS, they retain the ability to prime the adaptive arm of the immune system. This occurs in a saturable fashion following exposure to tumour and virally associated antigens. Such priming is shown to occur through the common heat shock protein receptor leading to phenotypic activation and stimulation of tetramer positive CD8 positive cytotoxic T cells. Depletion of CD8 positive T cells and of common and abundant heat shock proteins abrogates responses. Additionally, we show that interferon producing plasmacytoid dendritic cells are selectively depleted in KS positive compared to matched KS negative HIV-1 infected individuals. Interpretation: Functionally impaired dendritic cells can effectively cross-present immune responses via the common heat shock protein receptor. These results have important implications for the aetiopathogenesis of KS and for the development and design of any compounds, including vaccines, derived from cellular lysates.
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