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The Ischemia-Responsive Protein 94 (Irp94) Activates Dendritic Cells through NK Cell Receptor Protein-2/NK Group 2 Member D (NKR-P2/NKG2D) Leading to Their Maturation¹

Centre for Cellular and Molecular Biology, Hyderabad, India

Tumor recognition and killing, the uptake of released immunogenic substrate, and the generation of immunity are crucial aspects of dendritic cell (DC)-mediated antitumor immune response. In the context of direct tumoricidal activity, we have recently shown NK cell receptor protein-2 (NKR-P2)/NK group 2 member D (NKG2D) as a potent activation receptor on rat DCs. The activation of DCs with agonistic anti-NKR-P2 mAb, the binding of soluble NKR-P2 to the AK-5 tumor, and DC maturation with fixed AK-5 cells led us to identify a putative NKR-P2 ligand on the AK-5 cell surface. In this study we have shown that the AK-5 tumor-derived ischemia-responsive protein-94 (Irp94, a 110 kDa Hsp family member) acts as a functional ligand for NKR-P2 on DCs and enhances Irp94-NKR-P2 interaction-dependent tumor cell apoptosis via NO. Surface expression of Irp94 was also found on tumors of diverse origin in addition to AK-5. Furthermore, the Th1-polarizing cytokine IL-12, produced from Irp94-ligated BMDCs, augments NK cell cytotoxicity. Irp94-NKR-P2 interaction drives the maturation of BMDCs by up-regulating MHC class II, CD86, and CD1a and also induces autologous T cell proliferation, which displays a crucial state of DCs for adaptive antitumor immune response. These functional properties of Irp94 reside in the COOH terminus subdomain but not in the NH₂ terminus ATPase domain of Irp94. We also show the involvement of PI3K, ERK, protein kinase C, phosphatases, and NF-B translocation as downstream mediators of DCs activation upon NKR-P2 ligation with Irp94. Our studies demonstrate for the first time a novel role of a 110-kDa heat shock protein (Irp94) as a ligand for NKR-P2 on DCs, which in turn executes both innate and adaptive immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from Department of Biotechnology, Government of India. R.M.S. is a recipient of Council for Scientific and Industrial Research fellowships.

² Address correspondence and reprint requests to Dr. Ashok Khar, Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, AP 500007, India. E-mail address: khar{at}ccmb.res.in

³ Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived DC; CHO, Chinese hamster ovary; cIrp94, COOH terminus subdomain Irp94; ELIFA, enzyme-linked immunofiltration assay; FlIrp94, full-length Irp94; Hsp, heat shock protein; iNOS, inducible NO synthase; Irp94, ischemia-responsive protein 94; L-NAME, N^G-nitro-L-arginine methyl ester; MFI, mean fluorescence intensity; MICA/B, MHC class I-related chain A or chain B; MULT1, murine UL16-binding protein-like transcript 1; nIrp94, NH₂ terminus ATPase Irp94; NKG2D, NK group 2 member D; PMB, polymyxin B; sNKR-P2, soluble NKR-P2; NKR-P1 or -2, NK cell receptor protein-1 or -2; SDC, splenic DC.