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Functional Analysis of Killer Ig-Like Receptor-Expressing Cytomegalovirus-Specific CD8⁺ T Cells¹

Lars T. van der Veken^*, Maria Diez Campelo^*, Menno A. W. G. van der Hoorn^*, Renate S. Hagedoorn^*, H. M. Esther van Egmond^*, Jeroen van Bergen^2,, Roel Willemze^*, J. H. Frederik Falkenburg^* and Mirjam H. M. Heemskerk^2,*

^* Department of Hematology, Laboratory of Experimental Hematology and Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands

Killer Ig-like receptors (KIR) are expressed by human NK cells and T cells. Although Ag-specific cytolytic activity and cytokine production of KIR⁺ T cells can be inhibited by KIR ligation, the effect of KIR on proliferation is unclear. KIR⁺ T cells have been reported to have a general proliferative defect. To investigate whether KIR⁺ T cells represent end-stage dysfunctional T cells, we characterized KIR⁺ CMV-specific T cells in allogeneic stem cell transplantation patients and healthy donors. In both patients and healthy donors, a significant percentage KIR⁺ T cells was detected at various time points. All stem cell transplantation patients studied showed KIR expression on CMV-specific T cells, while not all donors had KIR-expressing CMV-specific T cells. From two of the patients and one donor KIR⁺ CMV-specific T clones were isolated and analyzed functionally. T cells were detected that expressed KIR that could not encounter their corresponding KIR ligands in vivo, illustrating that KIR expression by these T cells was not based on functional selection but a random process. Our data demonstrate that KIR⁺ T cells are fully functional T cells that are only restricted in effector functions and proliferation upon KIR ligation. The level of KIR-mediated inhibition of the effector functions and proliferation depended on the strength of TCR stimulation. We observed no diminished general proliferative capacity and therefore we conclude that these T cells do not represent end-stage dysfunctional T cells.

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.

L.T.v.d.V. designed research, performed research, analyzed data and wrote the article; M.D.C. performed research, M.A.W.G.v.d.H. performed research; R.S.H. performed research; H.M.E.v.E. performed research; J.v.B. designed research; R.W. designed research; J.H.F.F. designed research and wrote the paper; and M.H.M.H. designed research, analyzed data, and wrote the article.

¹ This study was supported by Grant 2001-2490 from the Dutch Cancer Society.

² Address correspondence and reprint requests to Dr. Mirjam H. M. Heemskerk, Department of Hematology, Laboratory of Experimental Hematology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail address: MHMHeemskerk{at}LUMC.nl

³ Abbreviations used in this paper: KIR, killer Ig-like receptor; SCT, stem cell transplantation; NGFR, nerve growth factor receptor; DLI, donor lymphocyte infusion; eGFP, enhanced GFP.