Circulating PD-1+CXCR5−CD4+ T cells underlying the immunological mechanisms of IgG4-related disease

Abstract

Objective The aim was to study the pathological role of lymphocytes with a peripheral T helper-cell-like phenotype (PD-1 + CXCR5 − CD4 + ) in IgG4-related disease (IgG4-RD). Methods PD-1 + CXCR5 − CD4 + T cells in the blood of patients with IgG4-RD ( n = 53), patients with SS ( n = 16) and healthy volunteers ( n = 34) as controls were analysed by flow cytometry. Correlations between results obtained by flow cytometry and clinical parameters relevant to IgG4-RD were also analysed. Results The percentage and absolute number of PD-1 + CXCR5 − cells within total CD4 + T cells in IgG4-RD patients were significantly increased compared with those in healthy volunteers. Further analysis showed that there were marked positive correlations of the percentage of PD-1 + CXCR5 − CD4 + T cells with the serum level of IgG4 and the number of organs involved. Interestingly, granzyme A (GZMA) + cells were enriched in PD-1 + CXCR5 − CD4 + T cells, and the percentage and absolute number of GZMA + PD-1 + CXCR5 − CD4 + T cells were significantly elevated in IgG4-RD patients. Although no obvious change was observed in the percentage of total CD4 + T cells, the percentage and absolute number of PD-1 + CXCR5 − CD4 + T cells decreased in accordance with a reduction of serum IgG4 level after treatment with glucocorticoids. Conclusion In IgG4-RD, circulating CD4 + T-cell populations were composed of PD-1 + CXCR5 − cells, and the ratios of these cells were correlated with clinical manifestations of IgG4-RD. Further analysis of GZMA + PD-1 + CXCR5 − CD4 + T cells might lead to a deeper understanding of the pathogenesis of ectopic lymphoid follicles and the persistent inflammation in IgG4-RD.

Shared and distinct roles of T peripheral helper and T follicular helper cells in human diseases

“…30 Whereas previous studies indicated that these SLE parameters were highly correlated with the frequency of cTfh cells, 31 other studies indicated an even higher correlation with cTph cells than cTfh cells. 29 An increase in circulating Tph cells has also been observed in other autoimmune and inflammatory diseases, such as Sjögren's syndrome, 32 IgG4-related diseases (IgG4-RDs), 33,34 systemic sclerosis, 35 IgA nephropathy 36 and type I diabetes. 37 Some correlations were observed between the frequency of circulating Tph cells and disease activity and/or clinical parameters in these diseases.…”

New insights into IgG4-related disease: emerging new CD4+ T-cell subsets

“…Because fractalkine, which is a ligand of CX3CR1, is highly expressed by endothelial cells in submandibular glands of IgG4-DS (H. Yabe, R. Kamekura R, unpublished data), Tph cells might have a role in the initiation of inflammation and maintenance of chronic fibroinflammation in IgG4-RD, although influencing vascularities in the lesions [47]. Given that destructive inflammation is observed in IgG4-RD [Figure 1], our experimental evidence indicates that Tph-like (PD-1 + CXCR5 - CD4 + ) cells, which preferentially contain cytotoxic granules of GZMA, are responsible for such pathological changes in IgG4-RD [19 ▪▪ ]. In this study, we could not see abundant expression of IL21 mRNAs in Tph-like cells compared with those in Tfh cells from patients with IgG4-RD [19 ▪▪ ].…”

“…In addition, Gu-Trantien et al [45] reported that CD4 + T cells with a Tph cell-like phenotype were found in breast cancer tissues and that they have a possible regulatory function in immune responses against tumor cells. Based on these observations, we have first reported a possible pathological role of Tph cells in IgG4-RD [19 ▪▪ ]. Our results have shown that circulating PD-1 + CXCR5 − cells (including PD-1 hi CXCR5 − cells, thus collectively named Tph-like cells here) were significantly increased within CD4 + T cells in patients with IgG4-RD compared to those in healthy volunteers.…”

“…In addition, we found that such Tph-like cells frequently expressed GZMA, which is related to a cytotoxic property. Clinical remission achieved by treatment with glucocorticoids clearly led to a numerical reduction of Tph-like cells [19 ▪▪ ]. Taken together, our findings strongly suggest that circulating Tph-like cells play a pivotal role in the pathogenesis of IgG4-RD.…”

“…After such studies on CD4 + T cells, T follicular helper (Tfh) cells [11,12 ▪ ,13 ▪▪ ,14–16] and CD4 + cytotoxic T lymphocytes (CD4 + CTLs) [17 ▪▪ ,18 ▪ ] were suggested to play a cardinal role in the immunological settings of IgG4-RD. In addition to these CD4 + T cells, we have recently identified other new CD4 + T cell subsets including PD-1 hi CXCR5 - peripheral T helper (Tph)-like cells and T follicular regulatory (Tfr) cells in blood of patients with IgG4-RD and we found that they are significantly correlated with various clinical parameters [19 ▪▪ ] (F Ito, R Kamekura, unpublished data). Because of their function for secretion of chemokines such as CXCL13, which is a ligand of CXCR5, Tph cells have a potential role in the initiation of inflammation and subsequently lead to the characteristic immune responses in collaboration with CXCR5-expressing lymphocytes such as Tfh cells and B cells in lesions of IgG4-RD.…”