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B i l j a n a Z a f i r o v a 1 , S a n j a M a n d a r i 1 , R o n a l d A n t u l o v 1 , A s t r i d K r m p o t i 1 , H e l e n a J o n s s o n 2 , W a y n e M . Y o k o y a m a 2 , S t i p a n J o n j i 1 a n d B o j a n P o l i 1
1 D e p a r t m e n t o f H i s t ology and Embryology, University of Rijeka School of Medicine, B. Branchetta 20, HR-51000 Rijeka, Croatia
2Howard Hughes Medical Institute, Rheumatology Division, Washington University Medical Centre, 660 S. Euclid Ave, Box 8045, St. Louis, MO 63110 U.S.A
Objectives: NKG2D is a potent activating receptor on NK cells which acts as a molecular sensor for stress exposed cells expressing NKG2D ligands such as virally infected or tumor transformed cells. Although NKG2D is expressed on NK cell precursors (NKPs), it is not known whether NKG2D has any role in NK cell development. Therefore, our major goal was to investigate possible consequences of NKG2D-deficiency on the development, homeostasis and effector functions of NK cells.
Methods: We have generated NKG2D-deficient mice by targeting the Klrk-1 locus in ES cells derived from C57BL/6 mouse strain (Bruce 4). In this work we used flow cytometry analysis as well as different functional assays to analyse developmental NK cell subpopulations. We also tested effector functions of NKG2D-deficient NK cells in MCMV infection model.
Results: Here we provide evidence for dual role of NKG2D in the physiology of NK cells: one, rather regulatory, implicated in their development, homeostasis and survival, and, other, important for exerting their effector functions. We observed the following consequences of NKG2D deficiency on the NK cell development and homeostasis: a) faster division of NK cells; b) perturbation in size of NK cell subpopulations and, c) their augmented sensitivity to apoptosis. As expected, NKG2D-/- NK cells were considerably less responsive to tumor cell targets expressing NKG2D ligands, thus confirming the important role of NKG2D for exertion of their effector functions NKG2D-/- mice however showed an enhanced NK cell-mediated resistance to MCMV infection as a consequence of NK cell dysregulation.
Conclusion: Our study reveals a novel, yet unknown function of NKG2D in NK cell physiology. We have shown here for the first time $ & H J j l 1
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