Abstract
CD1d-restricted invariant natural killer T cells (iNKT cells) may play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Interleukin (IL)-15 is a pro-inflammatory cytokine which is over-expressed in SLE patients. In the present study, we investigated the iNKT cell expansion of mononuclear cells (MNCs) from SLE patients following 10 days’ culture with α-galactosylceramide (α-Galcer) and /or IL-15. We sought to determine the phenotypic and functional characteristics of the expanded iNKT cells compared to healthy controls and correlated with disease activity. We observed that 1. The percentages of Vα24+/Vβ11+ iNKT cells following 10-day incubation was lower in SLE groups compared to controls; 2. The percentages and absolute numbers of Vα24+/Vβ11+ iNKT cells were expanded by α-galactosylceramide (α-Galcer), and further enhanced with IL-15 in SLE patient, but the effect of IL-15 was much lower than controls; 3.IL-15 +α-Galcer expanded CD3+/CD56+ NKT-like cells from SLE patients, especially with active disease 4. The CD161+ Vα24+/Vβ11+ iNKT cells in SLE were more responsive to α-Galcer stimulation than the CD161- counterpart; 5. IL-15 decreased apoptosis of α-Galcer activated SLE iNKT cells; 6. IL-15 enhanced CD69, CD1d and CD11a expression on α-Galcer treated iNKT cells; 7. The IL-4 production of iNKT cells was decreased in SLE patients compared to controls; 8. IL-15 increased IFN-γ and IL-4 production of SLE iNKT cells; 8. IL-15 failed to augment the ability of iNKT cells to aid NK-mediated K562 cytolysis in SLE patients; 9. CD161 positivity, granzyme B and perforin expression of α-Galcer+IL-15 expanded iNKT cells correlated with C3 levels in SLE patients. Taken together, our results demonstrated numeric and functional deficiency of iNKT cells and their response to IL-15 in SLE patients. Our finding may provide insight for using adoptive iNKT cell therapy in autoimmune diseases.
Highlights
Invariant natural killer T cells are a group of innate non-conventional T cells which recognized glycolipids presented by CD1d
The combination of IL-15 and α-GalCer resulted in greater increase of the percentages of Invariant natural killer T (iNKT) cells compared to α-GalCer alone in controls (14.0±2.7% vs 5.5±1.4%, p = 0.016) and Systemic lupus erythematous (SLE) patients as well (2.0±0.5% vs 0.8±0.2%, p = 0.008)
The combination of IL-15 and α-GalCer resulted in greater increase of iNKT cell recovery ratio compared to α-GalCer alone in controls (128.7±54.2 vs. 11.3±5.6, p = 0.002) and SLE patients (50.4±34.7 vs. 2.0±0.4, p
Summary
Invariant natural killer T (iNKT) cells are a group of innate non-conventional T cells which recognized glycolipids presented by CD1d. They express a unique invariant TCRα chain (Vα24Jα18 in humans) and are activated by the glycolipid α-galactosylceramide (αGalcer) [1, 2]. Autoantibodies against self-antigen can be detected in SLE patients which implicate the dysfunction of B cell immune response [5]. The number of invariant TCR Vα24Jα18+ T cells are reduced in peripheral blood lymphocytes of patients with SLE [6, 7]. Poor proliferative response of iNKT cells to α-GalCer was found in SLE patients compared to controls [8]. Poor proliferative response of iNKT cells to α-GalCer was found in SLE patients compared to controls [8]. iNKT cell deficiency correlates with SLEDAI (a marker of disease activity) [9], suggesting that iNKT cells are important involved in the control of disease
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