Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins block distinct steps in transendothelial migration of effector memory CD4+ T cells by targeting different endothelial proteins

Thomas D. Manes, Simon Hoer, William A. Muller, Paul J. Lehner, Jordan S. Pober

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

ORFK3 (K3) and ORFK5 (K5) are Kaposi's sarcoma-associated herpesvirus-encoded E3 ubiquitin ligases that differentially reduce surface expression of various proteins in infected cells. In this study, we describe their effects on human dermal microvascular endothelial cells (ECs), a natural target of Kaposi's sarcoma-associated herpesvirus infection. TNF-treated human dermal microvascular ECs transduced to express K5 show reduced capacity to capture effector memory (EM) CD4+ T cells under conditions of venular shear stress. K5 but not K3 transduction significantly reduces ICAM-1 expression and the inhibition of T cell capture was phenocopied by small interfering RNA knockdown of ICAM-1 and by anti-ICAM-1 Ab blocking. Cotransduction with an ICAM-1 truncated construct not subject to K5 ubiquitylation restored EM CD4+ T cell capture. K3 transductants effectively capture EM CD4+ T cells, but fail to support their transendothelial migration (TEM) in response to TCR engagement by superantigen presented by the ECs, leaving intact chemokine-dependent TEM. K3 but not K5 transduction significantly reduces PECAM-1 expression, and the effect on TCR-induced TEM is phenocopied by small interfering RNA knockdown of PECAM-1 and by anti-PECAM-1 Ab blocking. TCR-dependent TEM was restored in K3 transductants cotransduced to express a mutant of PECAM-1 not subject to K3-induced ubiquitylation. EM CD4+ T cells lack any known PECAM-1 counter receptor, but heterophilic engagement of PECAM-1 can involve glycosaminoglycans. In addition, TCR-induced TEM, but not chemokine-induced TEM, appears to involve a heparan- or chondroitin-like molecule on T cells. These results both identify specific roles of K5 and K3 in immune evasion and further differentiate the processes of inflammatory chemokine- versus TCRdependent recruitment of human EM CD4+ T cells.

Original languageEnglish (US)
Pages (from-to)5186-5192
Number of pages7
JournalJournal of Immunology
Volume184
Issue number9
DOIs
StatePublished - May 1 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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