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Prepublished online as a Blood First Edition Paper on May 15, 2003; DOI 10.1182/blood-2003-03-0891.
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Blood, 1 September 2003, Vol. 102, No. 5, pp. 1806-1814
IMMUNOBIOLOGY
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
From the Department of Immunology, Division of Investigative Science,
Faculty of Medicine, Imperial College of Science, Technology and Medicine, The
Chelsea and Westminster Hospital, London, United Kingdom; and the Center for
Immunotherapy of Cancer and Infectious Diseases, University of Connecticut
School of Medicine, Farmington.
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.
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