iNKT Cells in Lupus Development
Received Date: Dec 02, 2016 / Accepted Date: Dec 10, 2016 / Published Date: Dec 20, 2016
Invariant natural killer T (iNKT) cells are a new subset of T cells that bridge innate and acquired immunity and play important roles in both protective and regulatory responses in a variety of diseases [1,2]. Our group has worked on the role and the underlying molecular mechanisms of iNKT cells in lupus development for more than a decade and published a dozen of research articles in peer reviewed journals. Here, we briefly summarize and comment our findings.
Several promising and important findings are made on the features and roles of iNKT cells in three murine models of lupus. Firstly, we revealed for the first time that iNKT cells were deficient in both number and function in lupus-prone MRL-lpr mice. Moreover, repeated administration of α-GalCer, a glycolipid and natural activator of iNKT cells, expanded iNKT cell number and function in these mice . This finding revealed that α-GalCer was able to induce iNKT cell expansion in vivo. Before that, NKT cells were generally believed to undergo apoptosis upon α-GalCer treatment. Consistent to this finding, MRL-lpr mice with CD1d-deficiency, which blocks iNKT cell development, exacerbated the frequency and severity of skin lesions . Treatment with α-GalCer ameliorated the dermatitis in MRL-lpr mice . Secondly, in an induced lupus model in BALB/c mice by hydrocarbon oil pristane (2,6,10,14-tetramethylpentadecane, TMP), iNKT cells were found to be functionally insufficient. CD1-deletion in these mice further increased the level of serum autoAbs and induced more severe glomerulonephritis . In addition, repeated α-GalCer treatment of pristane-inoculated BALB/c mice prior to the onset of florid disease suppressed proteinuria . Thirdly, (NZB × NZW) F1 (BWF1) mice showed intrinsic deficiency of iNKT cell function . Deficiency of CD1 in BWF1 mice further worsened the glomerulonephritis as compared to wild-type mice . Similar findings are evident in β2-microglobulin knockout BWF1 mice, where iNKT cells are also deficient as CD1 knockout mice . Interestingly, activation of iNKT cells with α-GalCer in BWF1 mice at an early age by short term ameliorated the glomerulonephritis . Moreover, iNKT cells can directly regulate autoreactive B cells in a contact and CD1-dependent manner. This regulation was related to the impaired IL-10 production from B cells, reduced number and function of marginal zone B cells and involved Fas pathway [11,12].
The above studies indicate the regulatory role of iNKT cells in lupus development. These findings should be helpful to delineate the pathogenesis of lupus and may have the potential leading to new therapeutics for lupus, and perhaps other autoimmune diseases, based on manipulation of iNKT cells. Further in-depth studies are needed to explore the underlying molecular mechanisms how iNKT cells control lupus development.
- Bendelac A, Savage PB, Teyton L (2007) The biology of NKT cells. Annu Rev Immunol 25: 297-336.
- Wu L, Gabriel CL, Parekh VV, Van Kaer L (2009) Invariant natural killer T cells: innate-like T cells with potent immunomodulatory activities. Tissue Antigens 73: 535-545.
- Yang JQ, Saxena V, Xu H, Van Kaer L, Wang CR, et al. (2003) Repeated alpha-galactosylceramide administration results in expansion of NK T cells and alleviates inflammatory dermatitis in MRL-lpr/lpr mice. J Immunol 171: 4439-4446.
- Yang JQ, Chun T, Liu H, Hong S, Bui H, et al. (2004) CD1d deficiency exacerbates inflammatory dermatitis in MRL-lpr/lpr mice. Eur J Immunol 34: 1723-1732.
- Yang JQ, Singh AK, Wilson MT, Satoh M, Stanic AK, et al. (2003) Immunoregulatory role of CD1d in the hydrocarbon oil-induced model of lupus nephritis. J Immunol 171: 2142-2153.
- Singh AK, Yang JQ, Parekh VV, Wei J, Wang CR, et al. (2005) The natural killer T cell ligand alpha-galactosylceramide prevents or promotes pristane-induced lupus in mice. Eur J Immunol 35: 1143-1154.
- Yang JQ, Kim PJ, Halder RC,Singh RR(2013) Intrinsic hyporesponsiveness of invariant natural killer T cells precedes the onset of lupus. ClinExpImmunol 173: 18-27.
- Yang JQ, Wen X, Liu H, Folayan G, Dong X, et al. (2007) Examining the role of CD1d and natural killer T cells in the development of nephritis in a genetically susceptible lupus model. Arthritis Rheum 56: 1219-1233.
- Singh RR, Yang JQ, Kim PJ, Halder RC (2013) Germline deletion of beta2 microglobulin or CD1d reduces anti-phospholipid antibody, but increases autoantibodies against non-phospholipid antigens in the NZB/W F1 model of lupus. Arthritis Res Ther 15: R47.
- Yang JQ, Kim PJ, Singh RR (2012) Brief Treatment with iNKT Cell Ligand alpha-Galactosylceramide Confers a Long-term Protection Against Lupus. J ClinImmunol 32: 106-113.
- Yang JQ, Wen X, Kim PJ,Singh RR (2011) Invariant NKT cells inhibit autoreactive B cells in a contact- and CD1d-dependent manner. J Immunol 186: 1512-1520.
- Wen X, Yang JQ, Kim PJ,Singh RR (2011) Homeostatic regulation of marginal zone B cells by invariant natural killer T cells. PLoS One 6: e26536.
Citation: Yang JQ, Singh RR (2016) iNKT Cells in Lupus Development. Lupus Open Access 1:e103.
Copyright: © 2016 Yang JQ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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