Modulatory function of invariant natural killer T cells in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with complex immunological and clinical manifestations. Multiple organ failure in SLE can be caused by immune dysfunction and deposition of autoantibodies. Studies of SLE-susceptible loci and the cellular and humoral immune responses reveal variable aberrations associated with this systemic disease. Invariant natural killer T (iNKT) cells are a unique subset of lymphocytes that control peripheral tolerance. Mounting evidence showing reductions in the proportion and activity of iNKT cells in SLE patients suggests the suppressive role of iNKT cells. Studies using murine lupus models demonstrate that iNKT cells participate in SLE progression by sensing apoptotic cells, regulating immunoglobulin production, and altering the cytokine profile upon activation. However, the dichotomy of iNKT cell actions in murine models implies complicated interactions within the body's milieu. Therefore, application of potential therapy for SLE using glycolipids to regulate iNKT cells should be undertaken cautiously.

Figure 1

The function of iNKT cells in murine lupus models. iNKT cells in the mouse that express invariant TCR, Vα14Jα18, are CD1d-restricted T lymphocytes. The antigens presented by CD1d can be microbial components, endogenous antigen, iGb3, or oxidized lipid (Ox-lipid) derivatives from apoptotic cells. DCs and monocytes are potent APCs that activate iNKT cells both directly through TCR engagement and indirectly through IL-12. Immediately upon activation, iNKT cells release Th1-, Th2-, and T17-related cytokines, depending on the antigen presented and/or the characteristics of the APCs. The proinflammatory cytokines, IFN-γ and IL-17, lead predominantly to SLE exacerbation. iNKT cells can sense apoptotic blebs through Tim-1, which recognizes phosphatidylserine (PtdSer) exposed on the outer leaflet membrane, and can mediate immune suppression (see text). By contrast, iNKT cells activate B cells and thus upregulate total IgG and IgM levels in a CD1d-dependent manner, but iNKT cells can also inhibit the activation of autoreactive B cells. CD1d expression levels suggest that iNKT cells are capable of discriminating self- from nonself-reactive B cells.