TGF-β3 in differentiation and function of Tph-like cells and its relevance to disease activity in patients with systemic lupus erythematosus

Abstract

Objectives T peripheral helper (Tph) cells have major roles in pathological processes in systemic lupus erythematosus (SLE). We sought to clarify the mechanisms of Tph cell differentiation and their relevance to clinical features in patients with SLE. Method Phenotypes and functions of Tph cell–related markers in human CD4+ T cells purified from volunteers or patients were analyzed using flow cytometry and quantitative PCR. Renal biopsy specimens from patients with lupus nephritis (LN) were probed by multicolor immunofluorescence staining. Results Among multiple cytokines, transforming growth factor (TGF)-β3 characteristically induced programmed cell death protein 1 (PD-1) hi musculoaponeurotic fibrosarcoma (MAF)+, interleukin (IL)-21+IL-10+ Tph-like cells with a marked upregulation of related genes including PDCD-1, MAF, SOX4, and CXCL13. The induction of Tph-like cells by TGF-β3 was suppressed by the neutralization of TGF-β type II receptor (TGF-βR2). TGF-β3-induced Tph-like cells efficiently promoted the differentiation of class-switch memory B cells into plasmocytes, resulting in enhanced antibody production. The proportion of Tph cells in the peripheral blood was significantly increased in patients with SLE than in healthy volunteers in concordance with disease activity and severity of organ manifestations such as LN. TGF-β3 was strongly expressed on macrophages, which was associated with the accumulation of CD4+ C-X-C chemokine receptor (CXCR5)-PD-1+ Tph cells, in the renal tissue of patients with active LN. Conclusion The induction of Tph-like cells by TGF-β3 mainly produced from tissue macrophages plays a pivotal role in the pathological processes of active LN by enhancing B cell differentiation in patients with SLE.

Upregulation of PD-1 and its ligands and expansion of T peripheral helper cells in the nephritic kidneys of lupus-prone BXSB-Yaa mice

“…Similarly, Bocharnikov et al and Shan et al reported that the frequency of PBMC-derived Tph cells was correlated with several SLE disease activity indices. 2,3 The sPD-1, sPD-L1, and sPD-L2 serum levels in 16-weekold BXSB-Yaa mice were significantly higher than those in 8week-old BXSB-Yaa and C57BL/6 mice and were correlated with clinical lupus activity in the present study. This is consistent with our previous report, in which the sPD-1 and sPD-L2 serum levels were increased in patients with SLE and associated with its disease activity.…”

“…2 In addition, T cell-B cell interactions within the peripheral inflamed sites can involve T peripheral helper (Tph) cells with distinct phenotypes from the germinal center Tfh cells. 3 Actually, Bocharnikov et al identified a highly expanded population of programmed cell death protein 1 (PD-1) high CXCR5 -CD4 + T cells in the peripheral blood mononuclear cells (PBMCs) of patients with LN, which were Tph cells that stimulated B cell responses via Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan interleukin-21 (IL-21). 2 In addition, the frequencies of Tph cells, but not Tfh cells, correlated with clinical disease activity, and the frequency of PD-1 high CD4 + T cells among the CD45 + leukocytes that were derived from LN kidney biopsy samples was increased.…”

“…This corresponded with the disease activity and organ manifestation severity, such as LN, and the accumulation of Tph cells was observed in the renal tissue of patients with active LN through immunofluorescence microscopy. 3 PD-1 (CD279) is a cell surface receptor that belongs to the extended CD28/cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) family. 4 PD-1 is inducibly expressed on peripheral CD4 + and CD8 + T-cells, natural killer T-cells, B-cells, and monocytes, as well as some subset of dendritic cells during activation, but is not expressed on unstimulated cells.…”

Th1-related transcription factors and cytokines in systemic lupus erythematosus

“…Interestingly, B cells from SLE patients cultured with TGF-β3 showed reduced B-cell survival, proliferation, and differentiation into plasmablasts and IgG, IgA, and IgM production and decreased the expression of IFN regulatory factor 4 (IRF4), B lymphocyte-induced maturation protein-1 (Blimp-1), X-box-binding protein 1 (XBP1), Smad1/5, and Syk ( 111 ). T peripheral helper (Tph)-like cells in SLE patients such as PD-1 hi MAF + cells, IL-21 + IL-10 + cells, and PD-1 hi CX3CR1 + cells stimulated with TGF-β3 showed increased proliferation of the cells and elevated expression of PDCD-1, SOX4, and CXCL13 ( 112 ). CXCR5 - PD-1 hi Tph cells cocultured with class-switch memory B cells in the presence of TGF-β3 revealed much class-switch memory B cells differentiated into plasmocytes and high expression of IgG and IgM, suggesting that TGF-β3 regulates differentiation and function of Tph-like cells in lupus ( 112 ).…”

“…T peripheral helper (Tph)-like cells in SLE patients such as PD-1 hi MAF + cells, IL-21 + IL-10 + cells, and PD-1 hi CX3CR1 + cells stimulated with TGF-β3 showed increased proliferation of the cells and elevated expression of PDCD-1, SOX4, and CXCL13 ( 112 ). CXCR5 - PD-1 hi Tph cells cocultured with class-switch memory B cells in the presence of TGF-β3 revealed much class-switch memory B cells differentiated into plasmocytes and high expression of IgG and IgM, suggesting that TGF-β3 regulates differentiation and function of Tph-like cells in lupus ( 112 ). Injection of the poly(lactic-co-glycolic acid) nanoparticle encapsulating TGF-β into lupus mice induced expansion of CD4 + Foxp3 + Treg cells and CD8 + Foxp3 + Treg cells and suppression of anti-dsDNA antibody and reduced renal disease ( 113 ).…”