Tissue-specific functions of invariant natural killer T cells

Abstract

Invariant natural killer T cells (iNKT cells) are an innate-like T cell subset that expresses an invariant T cell receptor (TCR) α-chain and recognizes lipids presented on CD1d. They secrete diverse cytokines and can influence many types of immune responses. Despite having highly similar TCR specificities, iNKT cells differentiate in the thymus into distinct subsets that are analogous to T helper 1 (T_H1), T_H2 and T_H17 cell subsets. Additional iNKT cell subsets that may require peripheral activation have also been described, including one that produces IL-10. In general, iNKT cells are non-circulating, tissue-resident lymphocytes, but the prevalence of different iNKT cell subsets differs markedly between tissues. Here, we summarize the functions of iNKT cells in four tissues in which they are prevalent, namely, the liver, the lungs, adipose tissue and the intestine. Importantly, we explain how local iNKT cell responses at each site contribute to tissue homeostasis and protection from infection but can also contribute to tissue inflammation and damage.

Fig. 1 |. Tissue distribution of iNKT cell subsets in mice.

The figure illustrates how distinct invariant natural killer T (iNKT) cell subsets preferentially localize in lymphatic and non-lymphatic tissues in C57Bl/6 mice. NKT1, NKT2, NKT17 and NKT10 cells are indicated in blue, green, red and orange, respectively. The figure depicts the relative frequency of each iNKT cell subset in different tissue sites, including liver, lungs, intestine and adipose tissue, which are the focus of this Review.

Fig. 2 |. iNKT cells in the liver sinusoids.

a | At steady state, invariant natural killer T (iNKT) cells patrol the liver sinusoids in a random crawling motion both with and against the flow of blood. CD1d is expressed on liver sinusoidal endothelial cells (LSECs), Kupffer cells, hepatocytes and other cells not indicated in the figure. b | Activation of iNKT cells by α-galactosyl ceramide (αGalCer) or cytokines (such as IL-12 and IL-18) causes arrest of the cells on LSECs and production of IFNγ. c | During Borrelia burgdorferi infection, the bacterial spirochaete is taken up by Kupffer cells and can enter the liver parenchyma. B. burgdorferi infection causes the arrest and expansion of iNKT cell populations, as well as their production of IFNγ. The activated iNKT cells form clusters with Kupffer cells in a CD1d-dependent manner. d | Chronic hepatic inflammation results in the expansion of iNKT cell populations and the production of IFNγ, IL-12 and tumour necrosis factor (TNF) by various cell types in the liver. iNKT cells can induce death of hepatocytes directly by apoptosis-mediating surface antigen FAS–FAS antigen ligand (FASL) interactions, or indirectly through production of IFNγ. IFNγ production by iNKT cells can also stimulate dendritic cells (DCs) to produce IL-12, which can lead to killing of hepatocytes. TCR, T cell receptor.

Fig. 3 |. iNKT cells in the lung.

a | In the steady-state lung of C57Bl/6 mice, NKT1 cells are the most numerous invariant natural killer T (iNKT) cell subset, and they are localized primarily in the vasculature; the same is true for the less abundant NKT2 cell subset. NKT17 cells are mainly found within the lung tissue, although there is also a small number that is found in the vasculature. In the airways, CD1d is expressed by alveolar macrophages, CD11b⁺ dendritic cells (DCs), CD103⁺ DCs and monocyte-derived DCs. b | Following pulmonary infection with Streptococcus pneumoniae, NKT1 and NKT17 cells rapidly extravasate into the lung tissue, and these populations expand. These processes are driven by chemokines, including CC-chemokine ligand (CCL17) from neutrophils, which draws iNKT cells into the tissue. Within 13 hours, NKT1 cells produce IFNγ and NKT17 cells produce IL-17. Additional neutrophils are recruited into the tissue and alveoli, and this recruitment is decreased when iNKT cells are absent. These pathways promote clearance of S. pneumoniae from the lungs. CCR4, CC-chemokine receptor 4.