A recent study published in Medicine (Baltimore) has demonstrated a strong association between increased circulating T peripheral helper (Tph) cells, higher disease activity, and elevated plasma transforming growth factor beta 1 (TGF-β1) levels in patients with systemic lupus erythematosus (SLE). These findings provide clinically relevant insight into the immunopathogenesis of SLE and highlight a potential cellular marker linked to active disease, particularly in patients with inflammatory arthritis.
Tph cells are a recently characterized subset of CD4⁺ T cells regarded as peripheral tissue counterparts of T follicular helper (Tfh) cells. Similar to Tfh cells, they express high levels of programmed cell death-1 (PD-1), inducible T-cell co-stimulator (ICOS), and HLA-DR, and are capable of driving B-cell differentiation into antibody-secreting plasma cells through interleukin-21 production. In contrast to Tfh cells, Tph cells lack expression of CXCR5, the chemokine receptor responsible for follicular homing, and instead express CCR2, CCR5, and CX3CR1, facilitating their migration to inflamed peripheral tissues. This migratory profile supports their role in sustaining local immune activation outside secondary lymphoid organs, a mechanism increasingly recognized in chronic autoimmune diseases.
In this study, 50 patients with SLE and 20 healthy controls were evaluated using flow cytometry to quantify circulating Tph cells, while plasma cytokines were measured by enzyme-linked immunosorbent assay. Patients with SLE exhibited a significantly higher proportion of Tph cells among peripheral blood mononuclear cells compared with healthy controls. Importantly, Tph cell frequencies were further increased in patients with SLE who had clinical arthritis, underscoring a potential role for these cells in musculoskeletal inflammation and synovial immune crosstalk.
From a clinical perspective, Tph cell frequency showed a significant positive correlation with disease activity index scores and with CD19+ B-cell prevalence, reinforcing the concept that Tph cells contribute to B-cell-driven autoimmunity in SLE. The observed association with B-cell expansion is particularly relevant given the central role of autoreactive B cells and plasma cells in immune complex formation, complement activation, and organ damage in lupus. These data suggest that Tph cells may serve as a functional link between T-cell activation and pathogenic B-cell responses in active disease.
Plasma TGF-β1 levels were also significantly elevated in patients with SLE and correlated positively with circulating Tph cell proportions. For clinicians, this finding is notable because TGF-β signaling has complex immunoregulatory and profibrotic effects and may influence T-cell differentiation, tissue inflammation, and long-term organ damage. The association between TGF-β1 and Tph expansion suggests a cytokine environment that may favor persistence of pathogenic helper T-cell subsets in SLE.
These findings have several implications for medical professionals. Circulating Tph cells may represent a biomarker of disease activity and inflammatory arthritis in SLE, potentially aiding in patient stratification and monitoring. Therapeutic strategies that disrupt Tph-mediated B-cell help, such as targeting IL-21 pathways, PD-1 or ICOS signaling, or chemokine-driven tissue trafficking, could complement existing B-cell-directed therapies. Although further longitudinal and interventional studies are needed, this work supports the evolving view that peripheral immune niches and T cell and B cell interactions outside lymphoid follicles are key drivers of disease activity in SLE and may offer new avenues for targeted intervention.
References
- Wu C, Su Y, Lan S, Liu J, Ding J, Wu H, Dai Y, Gao F, Yan Q. Increased Tph cells are associated with disease activity and elevated plasma TGF-β1 levels in systemic lupus erythematosus. Medicine (Baltimore). 2025 Nov 14;104(46):e45917.
- Seki N, Tsujimoto H, Tanemura S, Kojima S, Miyoshi F, Kikuchi J, et al. Cytotoxic Tph subset with low B-cell helper functions and its involvement in systemic lupus erythematosus. Commun Biol. 2024 Mar 6;7(1):277.