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

Persistent expansion of circulating CD4 + effector memory T cells (T EM ) in patients with granulomatosis with polyangiitis (GPA) suggests their fundamental role in disease pathogenesis. Recent studies have shown that distinct functional CD4 + T EM cell subsets can be identified based on expression patterns of chemokine receptors. The current study aimed to determine different CD4 + T EM cell subsets based on chemokine receptor expression in peripheral blood of GPA patients. Identification of particular circulating CD4 + T EM cells subsets may reveal distinct contributions of specific CD4 + T EM subsets to the disease pathogenesis in GPA. 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 + T EM 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 T EM 1, T EM 2, T EM 17, and T EM 17.1 cells, respectively. The percentage of CD4 + T EM cells was significantly increased in GPA patients in remission compared to HCs. Chemokine receptor co-expression analysis within the CD4 + T EM cell population demonstrated a significant increase in the proportion of T EM 17 cells with a concomitant significant decrease in the T EM 1 cells in GPA patients compared to HC. The percentage of T EM 17 cells correlated negatively with T EM 1 cells in GPA patients. Moreover, the circulating proportion of T EM 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 T EM 1 and T EM 17 cells is modulated in CMV- seropositive GPA patients. Our data demonstrates the identification of different CD4 + T EM cell subsets in peripheral blood of GPA patients based on chemokine receptor co-expression analysis. The aberrant balance between T EM 1 and T EM 17 cells in remission GPA patients, showed to be associated with disease pathogenesis in relation to organ involvement, and tendency to relapse.