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

Objective: This study aimed to investigate the role of the programmed cell death protein 1 (PD-1) pathway and T peripheral helper (Tph) cells in the pathogenesis of lupus nephritis using lupus-prone BXSB-Yaa mice.
Methods: Male BXSB-Yaa mice and age-matched male C57BL/6 mice were used. The expression of PD-1 and its ligands (programmed cell death 1 ligand-1, PD-L1 and programmed cell death 1 ligand-2, PD-L2) and the phenotypes of kidney-derived cells and splenocytes expressing these molecules were analyzed by immunofluorescence and flow cytometry.
Results: Nephritis spontaneously developed in 16-week-old but not in 8-week-old BXSB-Yaa or C57BL/6 mice. PD-1 was expressed on CD4(+) mononuclear cells (MNCs) that infiltrated the glomeruli of 16-week-old BXSB-Yaa mice. The frequency of CD4(+)PD-1(+)CXCR5-ICOS+ kidney-derived Tph cells was higher in 16-week-old than in 8-week-old BXSB-Yaa and C57BL/6 mice, whereas the frequency of CD4(+)PD-1(+)CXCR5(+)ICOS(+) kidney-derived T follicular helper (Tfh) cells was not significantly different between the mice. PD-L1 was constitutively expressed in the renal tubules. PD-L2 was expressed in the glomeruli of 16-week-old BXSB-Yaa mice. The frequency of PD-L1(high)CD11c(+)CD3-CD19- and PD-L2(+)CD11c(+)CD3-CD19- kidney-derived MNCs in 16-week-old BXSB-Yaa mice was significantly higher than that of the control mice. The percentage of kidney-derived Tph cells but not Tfh cells was correlated with the urinary protein levels in the nephritic mice.
Conclusion: The results of this study suggest that kidney-infiltrating PD-1(+) Tph cells expanded concomitantly with the upregulation of PD-L1 and PD-L2 in the kidneys and the progression of lupus nephritis.