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

Objectives: T peripheral helper (Tph) cells have major roles in pathological processes in 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 analysed using flow cytometry and quantitative PCR. Renal biopsy specimens from patients with LN were probed by multicolour immunofluorescence staining. Results: Among multiple cytokines, transforming growth factor (TGF)-beta 3 characteristically induced programmed cell death protein 1 (PD-1)(hi) musculoaponeurotic fibrosarcoma (MAF)(+), 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-beta 3 was suppressed by the neutralization of TGF-beta type II receptor (TGF-beta R2). TGF-beta 3-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-beta 3 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-beta 3 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.

Automated summary

This study found that in patients with SLE, the proportion of Tph cells is increased and is correlated with disease activity and severity of organ manifestations. Transforming growth factor (TGF)-beta 3 is highly expressed in macrophages and induces the generation of Tph-like cells, which enhances B-cell differentiation and antibody production.