Chemokine receptor co-expression reveals aberrantly distributed T H effector memory cells in GPA patients.

BACKGROUND: Persistent 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.

METHOD: Peripheral 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 TEM 1, TEM 2, TEM 17, and TEM 17.1 cells, respectively.

RESULTS: The 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 TEM 17 cells with a concomitant significant decrease in the TEM 1 cells in GPA patients compared to HC. The percentage of TEM 17 cells correlated negatively with TEM 1 cells in GPA patients. Moreover, the circulating proportion of TEM 17 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 TEM 1 and TEM 17 cells is modulated in CMV- seropositive GPA patients.

CONCLUSIONS: Our 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 TEM 1 and TEM 17 cells in remission GPA patients, showed to be associated with disease pathogenesis in relation to organ involvement, and tendency to relapse.