Intrinsic hyporesponsiveness of invariant natural killer T cells precedes the onset of lupus

Summary Patients with systemic lupus erythematosus ( SLE ) display reduced numbers and functions of invariant natural killer  T ( iNK T ) cells, which are restored upon treatment with corticosteroids and rituximab. It is unclear whether the iNK T cell insufficiency is a consequence of disease or is a primary abnormality that precedes the onset of disease. To address this, we analysed iNK T cell function at different stages of disease development using the genetically lupus‐susceptible NZB  ×  NZW F 1 ( BWF 1 ) model. We found that iNK T cell in‐vivo cytokine responses to an iNK T cell ligand α‐galactosylceramide (α‐ G al C er) were lower in BWF 1 mice than in non‐autoimmune BALB /c and major histocompatibility complex ( MHC) ‐matched NZB  ×  N / B 10. PL F 1 mice, although iNK T cell numbers in the periphery were unchanged in BWF 1 mice compared to control mice. Such iNK T cell hyporesponsiveness in BWF 1 mice was detected at a young age long before the animals exhibited any sign of autoimmunity. In‐vivo activation of iNK T cells is known to transactivate other immune cells. Such transactivated T and B cell activation markers and/or cytokine responses were also lower in BWF 1 mice than in BALB /c controls. Finally, we show that iNK T cell responses were markedly deficient in the NZB parent but not in NZW parent of BWF 1 mice, suggesting that BWF 1 might inherit the iNK T cell defect from NZB mice. Thus, iNK T cells are functionally insufficient in lupus‐prone BWF 1 mice. Such iNK T cell insufficiency precedes the onset of disease and may play a pathogenic role during early stages of disease development in SLE .