The role of invariant natural killer T cells in microbial immunity

Abstract

Invariant natural killer T cells (iNKT cells) are unique lymphocytes with characteristic features, such as expression of an invariant T-cell antigen receptor (TCR) α-chain, recognition of glycolipid antigens presented by CD1d molecules, and ability to rapidly produce large amounts of cytokines, including interferon-γ (IFN-γ) and interleukin 4 (IL-4) upon TCR stimulation. Many studies have demonstrated that iNKT cells participate in immune response against diverse microbes, including bacteria, fungi, protozoan parasites, and viruses. Generally, these cells play protective roles in host defense against infections. However, in some contexts they play pathogenic roles, by inducing or augmenting inflammation. Recent reports show that iNKT cells recognize glycolipid antigens from pathogenic bacteria including Streptococcus pneumoniae, and they contribute to host defense against infection. iNKT cell responses to these microbial glycolipid antigens are highly conserved between rodents and humans, suggesting that iNKT cells are evolutionally conserved because their invariant TCR is useful in detecting certain pathogens. Furthermore, glycolipid-mediated iNKT cell activation during immunization has adjuvant activity, enhancing humoral and cell-mediated responses. Therefore, iNKT cell activation is an attractive target for developing new vaccines for infectious diseases.

Figure 1. Structures of the glycolipid antigens for iNKT cells

Structures of αGalCer, galacturonic acid (GalA) containing glycosphingolipid (GalAGSL) and glucuronic acid (GlcA) containing GSL (GlcAGSL) from Sphingomonas bacteria, Borrelia burgdorferi glycolipid (BbGL)-IIc, and glucosyl-diacylglycerol (Glc-DAG-s2) from Streptococcus pneumoniae are shown. The asterisk indicates that the 2-hydroxyl on the acyl chain of GalAGSL is sometimes present in bacteria.

Figure 2. iNKT cell activation augments innate and acquired immunity

Upon activation through recognition of glycolipid antigens (Ag) presented by CD1d molecules on DCs, iNKT cells start to express CD40L and produce IFNγ and IL-4. Subsequently, activated iNKT cells promote activation of DCs through cytokines and the CD40-CD40L interaction. In return, DCs secrete IL-12, which stimulates IFNγ production by iNKT cells and NK cells, leading to further stimulation of DCs in a positive feedback loop. DC activation induces maturation leading to enhanced priming of CD4 and CD8 T cells. CD4 T cells provide help to B cells for antibody production. Collectively, iNKT cell activation augments both innate and acquired immunity.