Abstract
Natural killer (NK) cells are innate immune cells able to rapidly kill virus-infected and tumor cells. Two NK cell populations are found in the blood; the majority (90%) expresses the CD16 receptor and also express the CD56 protein in intermediate levels (CD56Dim CD16Pos) while the remaining 10% are CD16 negative and express CD56 in high levels (CD56Bright CD16Neg). NK cells also reside in some tissues and traffic to various infected organs through the usage of different chemokines and chemokine receptors. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human virus that has developed numerous sophisticated and versatile strategies to escape the attack of immune cells such as NK cells. Here, we investigate whether the KSHV derived cytokine (vIL-6) and chemokines (vMIP-I, vMIP-II, vMIP-III) affect NK cell activity. Using transwell migration assays, KSHV infected cells, as well as fusion and recombinant proteins, we show that out of the four cytokine/chemokines encoded by KSHV, vMIP-II is the only one that binds to the majority of NK cells, affecting their migration. We demonstrate that vMIP-II binds to two different receptors, CX3CR1 and CCR5, expressed by naïve CD56Dim CD16Pos NK cells and activated NK cells, respectively. Furthermore, we show that the binding of vMIP-II to CX3CR1 and CCR5 blocks the binding of the natural ligands of these receptors, Fractalkine (Fck) and RANTES, respectively. Finally, we show that vMIP-II inhibits the migration of naïve and activated NK cells towards Fck and RANTES. Thus, we present here a novel mechanism in which KSHV uses a unique protein that antagonizes the activity of two distinct chemokine receptors to inhibit the migration of naïve and activated NK cells.
Highlights
Natural killer (NK) cells are innate immune lymphocytes that comprise approximately 10% of peripheral blood lymphocytes and are phenotypically characterized by the presence of CD56, the expression of NKp46, and the lack of CD3 expression [1]
We show that viral macrophage inflammatory protein (vMIP)-II binds and inhibits the activity of two different receptors, CX3CR1 and CCR5, expressed by naıve NK cells and by activated NK cells, respectively
It has been previously suggested that the viral chemokines encoded by Kaposi’s sarcoma-associated herpesvirus (KSHV) bind a wide spectrum of CC and CXC chemokine receptors [31]
Summary
NK cells are innate immune lymphocytes that comprise approximately 10% of peripheral blood lymphocytes and are phenotypically characterized by the presence of CD56, the expression of NKp46, and the lack of CD3 expression [1]. Mature NK cells predominantly circulate in the peripheral blood, they reside in several lymphoid and non-lymphoid organs, such as the spleen, tonsils, lymph nodes, liver, lungs, intestine, and the uterus [3]. In most of these organs the predominant NK cell population is CD56Bright CD16Neg [2,4]. This is reflected by the receptor repertoire expressed by the CD56Dim CD16Pos and CD56Bright CD16Neg NK cells, as the two subsets express a distinct set of inhibitory and activating receptors and display diversity in their adhesion molecules and chemokine receptors profile [1,2,3,4,5,6]
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