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Blood, 15 June 2006, Vol. 107, No. 12, pp. 4597-4605.
Prepublished online as a Blood First Edition Paper on March 2, 2006; DOI 10.1182/blood-2005-08-3207.
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CHEMOKINES, CYTOKINES, AND INTERLEUKINS
Chemokine receptor targeting efficiently directs antigens to MHC class I pathways and elicits antigen-specific CD8+ T-cell responses
Roberta Schiavo,
Dolgor Baatar,
Purevdorj Olkhanud,
Fred E. Indig,
Nicholas Restifo,
Dennis Taub, and
Arya Biragyn
From the Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, Baltimore; the Research Resources Branch, National Institute on Aging/National Institutes of Health (NIH), Baltimore; and the Surgery Branch, National Cancer Institute, Bethesda, MD.
Chemokines are key controllers of cell trafficking and are involved in numerous pathologic and inflammatory conditions. However, the fate of a chemokine ligand, once it is endocytosed with its receptor, remains obscure. Here, using chemokine–tumor antigen fusion constructs, we demonstrate for the first time that chemokines are internalized to early/late endosomal and lysosomal compartments through a clathrin-dependent process and subsequently delivered to the cytosol for proteasomal processing, facilitating efficient cross-presentation to the TAP-1–dependent MHC class I processing pathway. These data not only elucidate the intracellular fate of chemokine ligands upon receptor uptake, but also demonstrate the superior carrier potency of chemokines for delivering self-antigens to both class I and II processing pathways to induce CD8+ and CD4+ T-cell responses.
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