Lysosomal α-Galactosidase Controls the Generation of Self Lipid Antigens for Natural Killer T Cells

Abstract

SUMMARY Natural Killer T (NKT) cells are lipid-reactive, CD1d-restricted T lymphocytes important in infection, cancer, and autoimmunity. In addition to foreign antigens, NKT cells react with endogenous self lipids. However, in the face of stimulating self antigen, it remains unclear how overstimulation of NKT cells is avoided. We hypothesized that constantly degraded endogenous antigen only accumulates upon inhibition of α-galactosidase A (α-Gal-A) in lysosomes. Here, we show that α-Gal-A deficiency caused vigorous activation of NKT cells. Moreover, microbes induced inhibition of α-Gal-A activity in antigen-presenting cells. This temporary enzyme block depended on Toll-like receptor (TLR) signaling and ultimately triggered lysosomal lipid accumulation. Thus, we present TLR-dependent negative regulation of α-Gal-A as a mechanistic link between pathogen recognition and self lipid antigen induction for NKT cells.

Nod1 and Nod2 Enhance TLR-Mediated Invariant NKT Cell Activation during Bacterial Infection

“…Blunted IFN-g production by iNKT cells, but not NK cells, in Nod1/2 2/2 mice during bacterial infection Intact TLR signaling is essential to mediate iNKT cell activation during bacterial infection (18,24). Specifically, deficiency in the adaptor molecule MyD88 abrogates iNKT cell response against S. typhimurium and L. monocytogenes (18,24).…”

“…Specifically, deficiency in the adaptor molecule MyD88 abrogates iNKT cell response against S. typhimurium and L. monocytogenes (18,24). S. typhimurium and L. monocytogenes are known to activate Nod1 and Nod2; in light of the findings described above, we assessed whether Nod1/2 could synergize with TLRs to potentiate iNKT cell activation during infection.…”

“…In addition, blocking experiments revealed that both CD1d-TCR interactions and IL-12, but not IL-23, are important in TLR4/Nod1/2 synergistic activation. The self-glycosphingolipids isoglobotrihexosylceramide (20,24) and, more recently, b-glucosylceramide (25) were shown to be involved in TLR4-mediated iNKT cell activation. Although we provide evidence that cooperative engagement of Nods and TLR4 increases IL-12 production, it remains to be elucidated whether Nod receptor activation affects the lipid repertoire presented by CD1d to iNKT cells.…”

“…The pattern recognition receptors (PRRs) involved include TLR4 (20,21), TLR9 (19) (TLR8 in humans) (22), TLR7 (13), Rig-I (13), and Dectin-1 (23). Although the self-lipid species implicated remain poorly characterized, they may include isoglobotrihexosylceramide (20,24) and b-glucosylceramide (25). Finally, iNKT cells can be activated in a CD1d-independent, but IL-12-dependent, manner (26), suggesting that this cytokine can bypass the need for TCR engagement in certain circumstances.…”

Structural determination of lipid antigens captured at the CD1d–T-cell receptor interface

“…Identification of CD1d-presented lipid antigens has largely relied on indirect evidence, such as extrapolation from cells deficient in lipid synthesis genes (22,33), or fractionation of crude lipid sources with activity tracking within these fractions (14,20). These approaches have been useful, but do not directly demonstrate recognition by the TCR, and rely on correlations between two or more assays.…”