Conversion of T Follicular Helper Cells to T Follicular Regulatory Cells by Interleukin‐2 Through Transcriptional Regulation in Systemic Lupus Erythematosus

Abstract

Objective. This study was undertaken to identify characteristics of follicular regulatory T (Tfr) cells and elucidate the mechanisms by which follicular helper T (Tfh) cells convert to Tfr cells. We probed the phenotype of T helper cells in patients with systemic lupus erythematosus (SLE) and underlying transcriptional regulation using cytokine-induced STAT family factors. Methods. Peripheral blood mononuclear cells from 41 patients with SLE and 26 healthy donors were used to sort out the memory Tfh cell subset, and Tfh cells were cultured under various conditions. The phenotype of T helper cells and underlying mechanisms of transcriptional regulation were probed using flow cytometry and quantitative polymerase chain reaction analyses. These analyses evaluated the expression of characteristic markers and phosphorylation of STATs. Chromatin immunoprecipitation was used to evaluate histone modifications. Results. In patients with SLE, the proportion of CD4+CXCR5+FoxP3-PD-1 high Tfh cells was increased (P < 0.01), whereas the proportion of CD4+CXCR5+CD45RA-FoxP3 high activated Tfr cells was decreased (P < 0.05). Serum interleukin-2 (IL-2) levels were also reduced in patients with SLE. IL-2 induced conversion of memory Tfh cells to functional Tfr cells, which was characterized by CXCR5+Bcl-6+FoxP3 high pSTAT3+pSTAT5+ cells. The loci of FOXP3 and BCL6 at STAT binding sites were marked by bivalent histone modifications. Following IL-2 stimulation, STAT3 and STAT5 selectively bound to FOXP3 and BCL6 gene loci accompanied by suppression of H3K27me3. Finally, IL-2 stimulation suppressed the generation of CD38+CD27 high plasmablasts in Tfh and B cell coculture assays ex vivo. Conclusion. Impaired function of Tfr cells might be attributed to defective IL-2 production. Exogenous IL-2 restores the function of Tfr cells through the conversion of Tfh cells to Tfr cells in patients with SLE. Thus, restoring balance between Tfh and Tfr cells may provide new therapeutic approaches in SLE.

Impaired Function of PD-1+ Follicular Regulatory T Cells in Systemic Lupus Erythematosus

“…TFH and TFR cells have been proposed to play a critical role in SLE as defects within TFR cells could prevent suppression of TFH cells that stimulate production of possibly autoreactive antibodies. Studies regarding circulating TFR cell numbers in SLE patients have generated controversial results (8,9,13) but we observed no quantitative differences within our cohort. Instead, our results identi ed impaired suppression of TFH cells in SLE-TFR cells.…”

Multi-Source Pathways of T Follicular Helper Cell Differentiation

“…Tfr cells are able to access B-cell follicles and inhibit the Tfh–B cell response in GCs ( 6 ), which is indispensable for Tfh differentiation. Many reports have shown that alterations in the proportions of Tfh subsets and Tfr cells are associated with the pathogenesis of autoimmune and infectious diseases ( 7 – 11 ). The functional heterogeneity of Tfh cells suggests that multiple sources may contribute to the formation of terminally differentiated Tfh cells, which have developed the characteristics of their respective subsets and maintain the capacity for repolarization.…”

“…However, our recent study showed that IL-2 induced the transformation of human Tfh cells into Tfr-like cells. ChIP experiments showed that while promoting Foxp3 expression, IL-2 also maintained Bcl6 gene expression via activation of STAT3 ( 11 ). Therefore, IL-2-STAT5 should be considered a regulator of Tfr differentiation rather than a pure inhibitor.…”

Frontiers of Autoantibodies in Autoimmune Disorders: Crosstalk Between Tfh/Tfr and Regulatory B Cells

“…Another explanation for cTfr increasing in some studies may be that the proportion of activated cTfr cell subsets is reduced, although overall cTfr cells are increased, ultimately leading to an excessive GC response. Consistently, studies of SLE patients have indicated that the active phenotypes of cTfh and cTfh cells are altered and might lead to autoimmunity, whereas overall cTfh and cTfr cells are not significantly different between patients and healthy controls ( 107 ). The recent description of Th2- and Th17-like cell subsets of cTfr cells representing ongoing humoral responses in pSS also supports the imbalance of cTfr subsets in autoimmune diseases to some extent ( 125 ).…”

“…Indeed, the interactions of Tfh and Tfr cells are more complex than discussed above. Recent evidence indicates that Tfh cells can convert into Tfr cells in an IL-2 dependent manner, providing new insights into regulation of Tfr/Tfh balance ( 107 ). Moreover, in a breakthrough discovery, Wu et al ( 108 ) found a distinct subset of Tfh cells that could promote Tfr cell differentiation by blocking the Wnt-β-catenin axis in a sclerostin domain-containing protein 1-dependent (SOSTDC-1) manner.…”