title: Increased frequency of CCR4+ and CCR6+ memory T-cells including CCR7+CD45RAmed very early memory cells in granulomatosis with polyangiitis (Wegener's).
abstract: BACKGROUND
  Chemokine receptors play an important role in mediating the recruitment of T cells to inflammatory sites. Previously, small proportions of circulating Th1-type CCR5+ and Th2-type CCR3+ cells have been shown in granulomatosis with polyangiitis (GPA). Wondering to what extent CCR4 and CCR6 expression could also be implicated in T cell recruitment to inflamed sites in GPA, we investigated the expression of CCR4 and CCR6 on T cells and its association with T cell diversity and polarization.
  
  
  METHODS
  Multicolor flow cytometry was used to analyze CCR4, CCR6, and intracellular cytokine expression of T cells from whole blood of GPA-patients (n = 26) and healthy controls (n = 20). CCR7 and CD45RA were included for phenotypic characterization.
  
  
  RESULTS
  We found a significant increase in the percentages of circulating CCR4+ and CCR6+ cells within the total CD4+ T cell population in GPA. In contrast, there was no difference in the percentages of CD8+CCR4+ and CD8+CCR6+ T cells between GPA and healthy controls. CCR4 and CCR6 expression was largely confined to central (TCM) and effector memory T cells (TEM, TEMRA). A significant increase in the frequency of CCR4+ and CCR6+ TEMRA and CCR6+ TCM was shown in GPA. Of note, we could dissect CCR4 and CCR6 expressing CCR7+CD45RAmed very early memory T cells (TVEM) from genuine CCR7+CD45RAhigh naïve T cells lacking CCR4 and CCR6 expression for peripheral tissue-migration within the CCR7+CD45RA+ compartment. The frequencies of CCR4+ and CCR6+ TVEM were also significantly increased in GPA. An increased percentage of IL-17+ and IL-22+ cells was detected in the CCR6+ cell subsets and IL-4+ cells in the CRR4+ cell subset when compared with CD4+ cells lacking CCR4 and CCR6 expression.
  
  
  CONCLUSIONS
  Increased frequencies of circulating CCR4+ and CCR6+ memory T cell subsets including hitherto unreported TVEM suggest persistent T cell activation with the accumulation of CCR4+ and CCR6+ cells in GPA. CCR4 and CCR6 could be involved in the recruitment of T cells including cytokine-producing subsets to inflamed sites in GPA.
authors.affiliation: Department of Rheumatology, Vasculitis Center UKSH and Clinical Center Bad Bramstedt, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Fagin
authors.forename: Silke
authors.initials: S
authors.lastname: Pitann
authors.forename: Wolfgang L
authors.initials: WL
authors.lastname: Gross
authors.forename: Peter
authors.initials: P
authors.lastname: Lamprecht
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D014890:Granulomatosis with Polyangiitis / Q000453:epidemiology / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007156:Immunologic Memory / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D055953:Microscopic Polyangiitis / Q000453:epidemiology / Q000276:immunology / Q000378:metabolism*; D008875:Middle Aged; D054398:Receptors, CCR4 / Q000096:biosynthesis* / Q000276:immunology; D054399:Receptors, CCR6 / Q000096:biosynthesis* / Q000276:immunology; D054400:Receptors, CCR7 / Q000096:biosynthesis* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D055815:Young Adult
chemical_list: C515354:CCR4 protein, human; C106311:CCR6 protein, human; C515370:CCR7 protein, human; D054398:Receptors, CCR4; D054399:Receptors, CCR6; D054400:Receptors, CCR7; D017493:Leukocyte Common Antigens