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 by human herpes virus 8 (HHV-8) binds to multiple chemokine receptors, however, its ability to control the initial recruitment of specific leukocyte subtypes from the peripheral circulation has not been fully clarified. Here we show that vMIP-II blocks the firm arrest and transmigration of monocytes or Th1-like T lymphocytes triggered by RANTES immobilized on activated human microvascular endothelium (HMVEC) under flow conditions. The internalization of the receptors CCR1 and CCR5 that mediate arrest and transmigration of these cells in response to RANTES was prevented by vMIP-II, supporting its role as an antagonist of CCR1 and CCR5. In contrast, vMIP-II triggered the firm arrest of eosinophils and Th2-like T cells by engaging CCR3, as confirmed by its down-regulation. Immunohistochemical analysis of HHV-8-associated Kaposi's sarcoma lesions marked by vMIP-II expression and mononuclear cell infiltration revealed a predominance of Th2-type CCR3(+) lymphocytes over 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 provide evidence for a immunomodulatory role of vMIP-II in directing inflammatory cell recruitment away from a Th1-type towards a Th2-type response and thereby facilitating evasion from cytotoxic reactions.
Weber
K S
KS
Institut für Prophylaxe der Kreislaufkrankheiten, Ludwig-Maximilians-Universität, München, Germany.
Gröne
H J
HJ
Röcken
M
M
Klier
C
C
Gu
S
S
Wank
R
R
Proudfoot
A E
AE
Nelson
P J
PJ
Weber
C
C
D065100:CCR5 Receptor Antagonists; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D018925:Chemokines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology*; D004705:Endocytosis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects; D019288:Herpesvirus 8, Human / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
C515300:CCR1 protein, human; C515350:CCR3 protein, human; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D018925:Chemokines; D007375:Interleukin-1; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; C108059:vMIP-II