title: Regulation and gene expression profiling of NKG2D positive human cytomegalovirus-primed CD4+ T-cells.
abstract: NKG2D is a stimulatory receptor expressed by natural killer (NK) cells, CD8(+) T-cells, and γδ T-cells. NKG2D expression is normally absent from CD4(+) T-cells, however recently a subset of NKG2D(+) CD4(+) T-cells has been found, which is specific for human cytomegalovirus (HCMV). This particular subset of HCMV-specific NKG2D(+) CD4(+) T-cells possesses effector-like functions, thus resembling the subsets of NKG2D(+) CD4(+) T-cells found in other chronic inflammations. However, the precise mechanism leading to NKG2D expression on HCMV-specific CD4(+) T-cells is currently not known. In this study we used genome-wide analysis of individual genes and gene set enrichment analysis (GSEA) to investigate the gene expression profile of NKG2D(+) CD4(+) T-cells, generated from HCMV-primed CD4(+) T-cells. We show that the HCMV-primed NKG2D(+) CD4(+) T-cells possess a higher differentiated phenotype than the NKG2D(-) CD4(+) T-cells, both at the gene expression profile and cytokine profile. The ability to express NKG2D at the cell surface was primarily determined by the activation or differentiation status of the CD4(+) T-cells and not by the antigen presenting cells. We observed a correlation between CD94 and NKG2D expression in the CD4(+) T-cells following HCMV stimulation. However, knock-down of CD94 did not affect NKG2D cell surface expression or signaling. In addition, we show that NKG2D is recycled at the cell surface of activated CD4(+) T-cells, whereas it is produced de novo in resting CD4(+) T-cells. These findings provide novel information about the gene expression profile of HCMV-primed NKG2D(+) CD4(+) T-cells, as well as the mechanisms regulating NKG2D cell surface expression.
authors.affiliation: Section of Biomedicine, Laboratory of Immunology, Faculty of Life Sciences, University of Copenhagen, Copenhagen, Denmark. hellejensen@fastmail.fm
authors.forename: Helle
authors.initials: H
authors.lastname: Jensen
authors.forename: Lasse
authors.initials: L
authors.lastname: Folkersen
authors.forename: Søren
authors.initials: S
authors.lastname: Skov
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*; D008297:Male; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: C497869:KLRD1 protein, human; C527085:KLRK1 protein, human; D051920:NK Cell Lectin-Like Receptor Subfamily D; D055655:NK Cell Lectin-Like Receptor Subfamily K