Mechanisms of innate lymphoid cell and natural killer T cell activation during mucosal inflammation

Abstract

Mucosal surfaces in the airways and the gastrointestinal tract are critical for the interactions of the host with its environment. Due to their abundance at mucosal tissue sites and their powerful immunomodulatory capacities, the role of innate lymphoid cells (ILCs) and natural killer T (NKT) cells in the maintenance of mucosal tolerance has recently moved into the focus of attention. While NKT cells as well as ILCs utilize distinct transcription factors for their development and lineage diversification, both cell populations can be further divided into three polarized subpopulations reflecting the distinction into Th1, Th2, and Th17 cells in the adaptive immune system. While bystander activation through cytokines mediates the induction of ILC and NKT cell responses, NKT cells become activated also through the engagement of their canonical T cell receptors (TCRs) by (glyco)lipid antigens (cognate recognition) presented by the atypical MHC I like molecule CD1d on antigen presenting cells (APCs). As both innate lymphocyte populations influence inflammatory responses due to the explosive release of copious amounts of different cytokines, they might represent interesting targets for clinical intervention. Thus, we will provide an outlook on pathways that might be interesting to evaluate in this context.

Figure 1

Conserved lineage diversification in ILCs and NKT cells. NKT cells as well as ILCs can be divided into three separate sublineages that resemble Th1, Th2, and Th17 subsets in conventional CD4-positive T cells. Group 1 ILCs are characterized by the expression of either T-bet (ILC1) or T-bet and Eomes (NK cells). Group 2 ILCs are defined by the expression of RORα and GATA3 as well as their ability to release Th2 cytokines. Three sublineages are summarized under the umbrella of group 3 ILCs. While NK cell receptor-negative ILC3s only depend on RORγt, lymphoid tissue-inducer (LTi) cells require the aryl hydrocarbon receptor (Ahr) in addition to RORγt. NK cell receptor-expressing ILC3s depend on three transcription factors, AhR, RORγt and T-bet.