T cell cytokine imbalance towards production of IFN‐γ and IL‐10 in NZB/W F1 lupus‐prone mice is associated with autoantibody levels and nephritis

Abstract

Objective: The role of T cell‐derived cytokine production in lupus is poorly understood. We analysed the cytokine production of CD4+ T cells in the NZB/W F1 mouse strain, the mouse model probably most closely resembling human systemic lupus erythematosus (SLE), and assessed whether a possible shift in the cytokines expressed is associated with age or disease activity.Methods: We used intracellular cytokine staining and flow cytometry to determine the cytokine expression of splenic CD4+ T cells for interferon‐γ (IFN‐γ), tumour necrosis factor‐α (TNF‐α), interleukin‐4 (IL‐4) and IL‐10. NZB/W F1 mice at different ages spanning 5 to 36 weeks were analysed, healthy Balb/c×NZW F1 (CWF1) mice were used as controls. Serum anti‐double‐stranded DNA (anti‐dsDNA) antibody levels were determined by enzyme‐linked immunosorbent assay (ELISA), and proteinuria and plasma creatinine were estimated using commercial test kits.Results: The cytokine profile of CD4+ T cells was shifted towards T‐helper 1 (Th1) cells and the frequencies of Th cells expressing IFN‐γ+ correlated with age, anti‐dsDNA‐immunoglobulin G (IgG) titre and proteinuria. An increased percentage of IL‐10 producers correlated positively with anti‐dsDNA‐IgG and proteinuria, and a small gain in IL‐4 producers correlated with plasma creatinine. Neither the percentage of IL‐10 producers nor IL‐4 producers showed a significant correlation with age. There was no significant change observed in the frequency of TNF‐α T cells. The IFN‐γ/IL‐4 ratio demonstrated an increasing shift towards a Th1‐type response during disease development that was not present in healthy mouse strains.Conclusion: The association between the frequencies of T cells expressing IFN‐γ and IL‐10 and clinical findings suggests a key role for these cells in the pathogenesis of lupus.