Chemokine receptor co-expression reveals aberrantly distributed TH effector memory cells in GPA patients

Abstract

BackgroundPersistent expansion of circulating CD4+ effector memory T cells (TEM) in patients with granulomatosis with polyangiitis (GPA) suggests their fundamental role in disease pathogenesis. Recent studies have shown that distinct functional CD4+ TEM cell subsets can be identified based on expression patterns of chemokine receptors. The current study aimed to determine different CD4+ TEM cell subsets based on chemokine receptor expression in peripheral blood of GPA patients. Identification of particular circulating CD4+ TEM cells subsets may reveal distinct contributions of specific CD4+ TEM subsets to the disease pathogenesis in GPA.MethodPeripheral blood of 63 GPA patients in remission and 42 age- and sex-matched healthy controls was stained immediately after blood withdrawal with fluorochrome-conjugated antibodies for cell surface markers (CD3, CD4, CD45RO) and chemokine receptors (CCR4, CCR6, CCR7, CRTh2, CXCR3) followed by flow cytometry analysis. CD4+ TEM memory cells (CD3+CD4+CD45RO+CCR7-) were gated, and the expression patterns of chemokine receptors CXCR3+CCR4-CCR6-CRTh2-, CXCR3-CCR4+CCR6-CRTh2+, CXCR3-CCR4+CCR6+CRTh2-, and CXCR3+CCR4-CCR6+CRTh2- were used to distinguish TEM1, TEM2, TEM17, and TEM17.1 cells, respectively.ResultsThe percentage of CD4+ TEM cells was significantly increased in GPA patients in remission compared to HCs. Chemokine receptor co-expression analysis within the CD4+ TEM cell population demonstrated a significant increase in the proportion of TEM17 cells with a concomitant significant decrease in the TEM1 cells in GPA patients compared to HC. The percentage of TEM17 cells correlated negatively with TEM1 cells in GPA patients. Moreover, the circulating proportion of TEM17 cells showed a positive correlation with the number of organs involved and an association with the tendency to relapse in GPA patients. Interestingly, the aberrant distribution of TEM1 and TEM17 cells is modulated in CMV- seropositive GPA patients.ConclusionsOur data demonstrates the identification of different CD4+ TEM cell subsets in peripheral blood of GPA patients based on chemokine receptor co-expression analysis. The aberrant balance between TEM1 and TEM17 cells in remission GPA patients, showed to be associated with disease pathogenesis in relation to organ involvement, and tendency to relapse.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1343-8) contains supplementary material, which is available to authorized users.

Unraveling the identity of FoxP3+ regulatory T cells in Granulomatosis with Polyangiitis patients

“…Our group and others previously demonstrated skewing towards a Th17 phenotype in GPA 22,30,31 and an expanded T effector memory population that persists during disease remission 8,9 . Our current finding is in line with these observations and suggests that the expanded non-suppressive FoxP3 + T cell subset with a memory phenotype may be an important source of proinflammatory cytokines.…”

“…ANCA-induced neutrophil-mediated tissue damage has classically been deemed the primary pathogenic mechanism 2 . However, accumulating evidence points towards an essential role for T cells in disease expression and progression: effector T cells are found in biopsies of inflamed renal and granulomatous tissue 3,4 ; ANCAs are class-switched autoantibodies and therefore necessitate T cell help 5 ; increased serum markers of T cell activation correlate with disease activity 6,7 ; and peripheral blood homeostasis of CD4+ T cells is disturbed with the persistent expansion of effector memory cells during remission 8,9 .…”

Effect of age and sex on immune checkpoint expression and kinetics in human T cells

“…To study the effect of age and sex on immune checkpoint expression, 20 healthy young adults (YA, median age and range in years: 26 (20–31), male/ female ratio 9/11) and 20 healthy older adults (OA, median age and range in years: 72 (54–86), male/female ratio 9/11) were enrolled in this study (Additional Table S 1 ). Since CMV serostatus has known effects on immune function and as CMV seropositivity increases with age [ 41 ], CMV serostatus was determined in all participants as described before [ 42 ]. CD40 expression by B cells was measured in all 20 YA and in 16 of the 20 OA.…”

The role of chemokines and chemokine receptors in multiple sclerosis

“…Different chemokine/chemokine receptors represent different immune responses types: CCR1, CCR5, and CXCR3 are a feature of Th-1 immune response, and CCR3, CCR4, and CCR10 are the feature of Th-2 immune response [1]. In addition, CCR4 and CCR6 are highly expressed in Th17 cells while CCR6 and CXCR3 are highly expressed in Th17.1 cells [1,67]. In humans and mice, chemokine receptors have different expression levels in memory T cells and effector cell subsets, providing specificity for cell trafficking in both homeostasis and inflammation.…”