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Functional Killer Ig-Like Receptors on Human Memory CD4⁺ T Cells Specific for Cytomegalovirus¹

Jeroen van Bergen^2,*, Engelina M. C. Kooy-Winkelaar^*, Henrike van Dongen, Floris A. van Gaalen, Allan Thompson^*, Tom W. J. Huizinga, Mariet C. W. Feltkamp, René E. M. Toes and Frits Koning^*

^* Department of Immunohematology and Blood Transfusion, Department of Rheumatology, and Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands

Although very few CD4⁺ T cells express killer Ig receptors (KIR), a large proportion of CD4⁺ T cells with a late memory phenotype, characterized by the absence of CD28, does express KIR. Here, we show that KIR expression on CD4⁺ T cells is also associated with memory T cell function, by showing that the frequency of CMV-specific cells is higher in CD4⁺KIR⁺ than CD4⁺KIR^– T cells. In addition, engagement of an inhibitory KIR inhibited the CMV-specific proliferation of these CD4⁺KIR⁺ memory T cells, but had no detectable effect on cytokine production. Our data reveal that, in marked contrast with CD8⁺ T cells, the activity of a subset of CMV-specific CD4⁺ T cells is modulated by HLA class I-specific KIR. Thus, the CMV-induced down-regulation of HLA class I may in fact enhance memory CMV-specific CD4⁺ T cell responses restricted by HLA class II.

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 J.v.B. was funded by VENI Grant 916.36.025, H.v.D. by Clinical Research Trainee Grant 920.03.259, and R.E.M.T. by VIDI Grant 016.046.365, all from the Netherlands Organization for Health Research and Development.

² Address correspondence and reprint requests to Jeroen van Bergen, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, the Netherlands. E-mail address: J.van_Bergen{at}lumc.nl

³ Abbreviations used in this paper: KIR, killer Ig-related receptor; RA, rheumatoid arthritis.