Association of circulating SLAMF7⁺Tfh1 cells with IgG4 levels in patients with IgG4-related disease

Background: Follicular helper CD4⁺ T (Tfh) cells have a critical role in IgG4 production by B cells in IgG4-related disease (IgG4-RD). Recent studies including ours showed that SLAMF7⁺CD4⁺ T cells are an important pathological driver of IgG4-RD. In this study, we have sought to elucidate a relationship between helper CD4⁺ T (Th), particularly Tfh, cells and SLAMF7⁺ CD4⁺ T cells in IgG4-RD. Results: The patients with IgG4-RD enrolled in this study were aged 66 ± 12 years and their titers of serum IgG4 were 372 ± 336 mg/dl. Th1 cells, activated circulating Tfh1 (cTfh1), and activated cTfh2 cells increased in IgG4-RD. SLAMF7 was mainly expressed on Th1 and cTfh1, but not cTfh2, cells in the patients. SLAMF7⁺ cTfh1 cells were PD-1/CD28 double-positive, whereas SLAMF7⁺ Th1 cells were CD28 negative. Positive correlations were noted between serum IgG4 levels and the number of activated cTfh2 cells and SLAMF7⁺ cTfh1 cells, but not SLAMF7⁺ Th1 cells. Intriguingly, among cTfh1 cells, activated SLAMF7⁺ cTfh1 cells were high producers of IL-10 along with IL-21. Blimp-1, but not Bcl-6, mRNA was expressed at high levels in activated SLAMF7⁺ cTfh1 cells. In addition to CD4⁺ T cells, the frequency of SLAMF7⁺ fraction was higher in memory B cells than naïve B cells in patients with IgG4RD. Finally, upon stimulation via B-cell receptor and CD40, Tfh1-associated cytokines, IL-21 and IFN-γ, most significantly induced SLAMF7 expression in memory B cells. Conclusions: Together, these results suggest that circulating SLAMF7⁺ Tfh1 cells, along with Tfh2 cells, play a pathologic role in IgG4 production in IgG4-RD.