The interaction between invariant Natural Killer T cells and the mucosal microbiota

Abstract

The surface of mammalian bodies is colonized by a multitude of microbial organisms, which under normal conditions support the host and are considered beneficial commensals. This requires, however, that the composition of the commensal microbiota is tightly controlled and regulated. The host immune system plays an important role in the maintenance of this microbiota composition. Here we focus on the contribution of one particular immune cell type, invariant Natural Killer T (iNKT) cells, in this process. The iNKT cells are a unique subset of T cells characterized by two main features. First, they express an invariant T-cell receptor that recognizes glycolipid antigens presented by CD1d, a non-polymorphic major histocompatibility complex class I-like molecule. Second, iNKT cells develop as effector/memory cells and swiftly exert effector functions, like cytokine production and cytotoxicity, after activation. We outline the influence that the mucosal microbiota can have on iNKT cells, and how iNKT cells contribute to the maintenance of the microbiota composition.

Keywords: invariant Natural Killer T cells; microbiota; mucosal immunology.

Figure 1

The route of invariant Natural Killer T (i NKT) cell activation impacts their effector function. For i NKT cells in unchallenged control mice, i.e. thymus‐derived i NKT cells, three routes of activation have been described. (a) In the direct or antigen‐dependent activation, a strong antigen, usually of foreign origin, binds to CD1d and activates i NKT cells via their semi‐invariant T‐cell receptor (TCR). αGalCer is depicted as an example. This direct activation leads to the production of both T helper type 1 (Th1) cytokines, like interferon‐γ (IFN‐γ) and tumour necrosis factor, and Th2 cytokines, like interleukin‐4 (IL‐4) and IL‐13, by the i NKT cells, which is sometimes referred to as a Th0 response. (b) The indirect or antigen‐independent activation does not require an engagement of TCR, but rather is achieved by the exposure of the i NKT cells to several pro‐inflammatory cytokines alone or in combination. Some cytokines could induce a preferential production of particular cytokines by the i NKT cells, leading to a Th1‐bias (more IFN‐γ and/or less IL‐4), Th2‐bias (more IL‐4, IL‐13 and/or less IFN‐γ), or Th17‐bias (more IL‐17A). The available data indicate a preferential activation of NKT17 cells in the case of the Th17‐bias. However, in the case of the Th1‐ and Th2‐biases it seems more likely that it is the result of a modulation of the i NKT cell cytokine response. (c) In the synergistic pathway the stimulation of i NKT cells depends both on the TCR and on cytokine receptors. In these cases, the stimulation provided by a weak antigen (signal 1) and sub‐optimal cytokine concentrations (signal 3), which are both too weak on their own to drive i NKT cell activation, can act together to achieve the stimulation of the i NKT cells. The antigens bound to CD1d could be of self or foreign origin. In the direct and synergistic pathways, the signal can also be amplified by the up‐regulation of the expression levels of CD1d97, 122 and/or self‐antigens.97, 98 Additionally, signal two, i.e. co‐stimulation/inhibition, can modulate i NKT cell responses.25

Figure 2

Graphic summary of the functions of invariant Natural Killer T (i NKT) cells at mucosal surfaces: (a) i NKT cells at mucosal surfaces can respond to many signals. Bacterium‐, fungus‐, and food‐derived products can influence the tissue‐resident cells of the mucosa and the local immune cells, via antigens, pathogen‐associated molecular patterns (PAMPs), and metabolites (Box 1). These can alter the frequency and function of various cells (not depicted). Antigens for i NKT cells can be either self‐antigens or antigens derived from the microbiota (Table 1). Some of the bacterially derived glycolipids binding to CD1d can also be inactive, competitive inhibitors. Furthermore, i NKT can respond to local cytokines either directly or synergistically with CD1d‐bound antigens. (b) Invariant NKT cells are known to influence the mucosal microenvironment and the microbial composition via (1) cytokines that they produce and (2) direct cell–cell contact. (1) Invariant NKT cell derived interferon‐γ (IFN‐γ) or interleukin‐13 (IL‐13) has been shown to activate Paneth cells or goblet cells to increase production of anti‐microbial peptides (AMPs) or mucus, respectively. Furthermore, i NKT cells have been shown to boost IgA and IgG production by B cells. Finally, CD1d^−/− mice had a lower frequency of CD304⁺ regulatory T (Treg) cells in the mesenteric lymph nodes and i NKT cell‐derived IL‐4 was implicated.46 (2) Binding of i NKT cells to CD1d can induce, via a CD1d‐retrograde signal, IL‐10 or IL‐22 production by epithelial cells or innate lymphoid cells (ILC3s), respectively, which both support mucosal integrity. Please note that the figure does not attempt to represent a particular mucosal surface, but summarizes available data derived from various tissues and sides. For additional references we refer to the main text and Box 1. AMPs, anti‐microbial peptides; ECs, epithelial cells.