Selective recruitment of Th2-type cells and evasion from a cytotoxic immune response mediated by viral macrophage inhibitory protein-II

The viral CC chemokine macrophage inhibitory protein-II (vMIP-II) encoded b y human herpes virus 8 (HHV-8) binds to multiple chemokine receptors, howev er, its ability to control the initial recruitment of specific leukocyte su btypes from the peripheral circulation has not been fully clarified. Here w e show that vMIP-II blocks the firm arrest and transmigration of monocytes or Th1-like T lymphocytes triggered by RANTES immobilized on activated huma n microvascular endothelium (HMVEC) under flow conditions. The internalizat ion of the receptors CCR1 and CCR5 that mediate arrest and transmigration o f these cells in response to RANTES was prevented by vMIP-II, supporting it s role as an antagonist of CCR1 and CCR5. In contrast, vMIP-II triggered th e firm arrest of eosinophils and Th2-like T cells by engaging CCR3, as conf irmed by its down-regulation. Immunohistochemical analysis of HHV-8-associa ted Kaposi's sarcoma lesions marked by vMIP-II expression and mononuclear c ell infiltration revealed a predominance of Th2-type CCR3(+) lymphocytes ov er Th1-type CXCR3(+)/CCR5(+) leukocytes, indicating that as a CCR3 agonist vMIP-II can drive a Th2-type immune response in vivo. Thus, our data provid e evidence for a immunomodulatory role of vMIP-II in directing inflammatory cell recruitment away from a Th1-type towards a Th2-type response and ther eby facilitating evasion from cytotoxic reactions.