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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1770-1778.
Prepublished online as a Blood First Edition Paper on November 6, 2003; DOI 10.1182/blood-2003-06-2114.
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IMMUNOBIOLOGY
The mechanisms controlling NK cell autoreactivity in TAP2-deficient patients
Gal Markel,
Huda Mussaffi,
Khoon-Lin Ling,
Mariolina Salio,
Stephan Gadola,
Guy Steuer,
Hannah Blau,
Hagit Achdout,
María de Miguel,
Tsufit Gonen-Gross,
Jacob Hanna,
Tal I. Arnon,
Udi Qimron,
Ilan Volovitz,
Lea Eisenbach,
Richard S. Blumberg,
Angel Porgador,
Vincenzo Cerundolo, and
Ofer Mandelboim
From the The Lautenberg Center for General and Tumor Immunology, Hadassah Medical School, Jerusalem, Israel; Pulmonary Unit, Schneider Children's Medical Center of Israel, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Tumour Immunology Unit, Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom; Pediatric Department, Assaf-Harofe Hospital, Zrifin, Israel; Department of Health and Experimental Sciences (DCEXS) (Inmunología), Barcelona, Spain; Department of Microbiology and Immunology, Faculty of Health Sciences, and The Cancer Research Center, Ben Gurion University, Beer-Sheva, Israel; Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; and Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
The killing of natural killer (NK) cells is regulated by activating and inhibitory NK receptors that recognize mainly class I major histocompatibility complex (MHC) proteins. In transporter associated with antigen processing (TAP2)–deficient patients, killing of autologous cells by NK cells is therefore expected. However, none of the TAP2-deficient patients studied so far have suffered from immediate NK-mediated autoimmune manifestations. We have previously demonstrated the existence of a novel class I MHC–independent inhibitory mechanism of NK cell cytotoxicity mediated by the homophilic carcinoembryonic antigen–related cell adhesion molecule 1 (CEACAM1) interactions. Here, we identified 3 new siblings suffering from TAP2 deficiency. NK cells derived from these patients express unusually high levels of the various killer cell inhibitory receptors (KIRs) and the CEACAM1 protein. Importantly, the patients' NK cells use the CEACAM1 protein to inhibit the killing of tumor and autologous cells. Finally, we show that the function of the main NK lysis receptor, NKp46, is impaired in these patients. These results indicate that NK cells in TAP2-deficient patients have developed unique mechanisms to reduce NK killing activity and to compensate for the lack of class I MHC–mediated inhibition. These mechanisms prevent the attack of self-cells by the autologous NK cells and explain why TAP2-deficient patients do not suffer from autoimmune manifestations in early stages of life.
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