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

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Abstract
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. We used intracellular cytokine staining and flow cytometry to determine the cytokine expression of splenic CD4(+) T cells for interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha), interleukin-4 (IL-4) and IL-10. NZB/W F1 mice at different ages spanning 5 to 36 weeks were analysed, healthy Balb/cxNZW 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. The cytokine profile of CD4(+) T cells was shifted towards T-helper 1 (Th1) cells and the frequencies of Th cells expressing IFN-gamma(+) 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-alpha T cells. The IFN-gamma/IL-4 ratio demonstrated an increasing shift towards a Th1-type response during disease development that was not present in healthy mouse strains. The association between the frequencies of T cells expressing IFN-gamma and IL-10 and clinical findings suggests a key role for these cells in the pathogenesis of lupus.