HHV8-encoded vMIP-I selectively engages chemokine receptor CCR8. Agonist and antagonist profiles of viral chemokines.
Uncertainty regarding viral chemokine function is mirrored by an incomplete knowledge of host chemokine receptor usage by the virally encoded proteins. One such molecule is vMIP-I, a C-C type chemokine of undefined function and binding specificity, encoded by the Kaposi's sarcoma herpesvirus HHV-8. We report here that vMIP-I binds to and induces cytosolic [Ca(2+)] signals in human T cells selectively through CCR8, a CC chemokine receptor associated with Th2 lymphocytes. Furthermore, using a panel of 65 different human, viral, and rodent chemokines, we have established a comprehensive ligand binding "fingerprint" for CCR8. The receptor exhibits marked "high" affinity (K(d) < 15 nM) only for four chemokines, three of them of viral origin: vMIP-I, vMIP-II, vMCC-I, and human I-309. A previously unreported second class of lower affinity ligands includes MCP-3 and possibly two other viral chemokines. vMIP-I and I-309 appear to act as CCR8 agonists: binding to and inducing cytosolic [Ca(2+)] elevation through the receptor. By contrast, vMIP-II and vMCC-I act as potent antagonists: binding without inducing signaling, and blocking the effects of I-309 and vMIP-I. These results suggest a ligand hierarchy for CCR8, identifying vMIP-I as a selective viral chemokine agonist. CCR8 may thus engage a specific subset of chemokines with the potential to regulate each other during viral infection and immune regulation.
Divisions of Discovery Biology and Molecular Pharmacology, ChemoCentryx, San Carlos, California 94070, USA.
D J
DJ
Dairaghi
R A
RA
Fan
B E
BE
McMaster
M R
MR
Hanley
T J
TJ
Schall
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D005434:Flow Cytometry; D019288:Herpesvirus 8, Human / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology*; D014764:Viral Proteins
C103330:CCR8 protein, human; D019742:Chemokines, CC; D007376:Interleukin-2; D019402:Macrophage Inflammatory Proteins; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D014764:Viral Proteins; C108459:vMIP-1 protein, Human herpesvirus 8; D002118:Calcium