Classification and Plasticity of ILCs
ILCs are novel subsets of lymphoid cells that lack antigen-specific receptors, making them distinct from T and B cells. They respond to a number of inflammatory cytokines such as IL-1, IL-18, IL-33, IL-23, and IL-25 (IL-1 and IL-12 family cytokines) and lipid mediators.14 Helper ILCs can be classified into ILC1, ILC2, ILC3 and lymphoid tissue inducer (LTi) subtypes based on their cytokine production and transcriptional profiles (Figure 1): in this regard, ILC1s, ILC2s and ILC3s resemble CD4+ T helper (Th)1, Th2 and Th17/22 cells, respectively.15, 16 LTi cells are indispensable for the initiation of secondary lymphoid organ development during embryonic life.17 Adult LTi cells are Neuropilin-1+ (NRP1+) ILC3-like cells that are key inducers of ectopic lymphoid aggregate (ELA) formation.18 In addition to this, natural killer (NK) cells represent the “cytotoxic” ILCs corresponding to CD8+ cytotoxic T cells.15,19
ILC1s are defined by the expression of T-bet (T-box expressed in T cells) transcription factor and can be activated by macrophage- and dendritic cell (DC)-derived IL-12 and IL-18. The activation of ILC1s lead to the production of interferon (IFN)-γ. Upon exposure to intracellular pathogens, an increase in ILC1 number is observed in order to protect against viruses and bacteria.20 They have been implicated in conditions like Crohn’s disease21, Celiac disease22 and chronic pulmonary obstructive disease (COPD).23
ILC2s are under the control of transcription factor GATA-3, and once activated by epithelium-derived IL-25, IL-33 and TSLP, they produce the type 2 cytokines IL-5 and IL-13.15, 23 The putative role of ILC2s have been defined in several diseases including allergic asthma24, 25, allergic rhinitis26, atopic dermatitis (AD)27 and eosinophilic esophagitis.13
ILC3s are divided into 2 different subtypes, which can be distinguished by the expression of the natural cytotoxicity receptor NKp44.28 Retinoic acid-related orphan receptor (RORγt) is the transcription factor for all ILC3 subtypes. ILC3s secrete IL-17, IL-22, granulocyte-macrophage colony-stimulating factor (GM-CSF) and/or tumor necrosis factor (TNF)-α in response to myeloid-derived IL-1β and IL-23.29 They can both promote or supress the immune response depending on the microenvironment and presence of cytokines within the tissues.30 Retinoic acid and active form of vitamin D (1,25‐dihydroxyvitamin D3) have antagonistic effects on the expression of effector cytokines and gut‐homing integrin by human ILCs. The balance between these vitamins may be an important factor in the functioning of ILCs in allergic disease, including food allergy.31
Activated CD40L+ ILC3s reside on the border of T cell–B cell areas in tonsils and are in close contact with B cells in vivo. CD40L+ ILC3s and B cells are a symbiotic relationship: ILC3s induce IL-15 production in B cells via BAFF-receptor, while IL-15, a potent growth factor for ILC3s, upregulate CD40L expression on ILC3s. IL-15-activated CD40L+ ILC3s help the differentiation of IL-10 secreting, functional immature transitional regulatory B cells in a CD40L- and BAFF-receptor-dependent manner. This contributes to the maintenance of immune tolerance to innocuous antigens and is thought to become insufficient in allergic diseases.32 Tonsils are a crucial site for the generation of functional allergen-specific Treg cells and are therefore important mucosal sites for the development of immune toleranc. ILC3s and Breg cells co-localize in the interfollicular regions of palatine tonsils, together with Treg cells. These data suggest that there are regulatory niches in tonsils.33
More extensive information on ILC surface markers and cytokine production can be found in recent reviews.28, 30,19 ILC3s have been associated with the pathology of inflammatory bowel diseases34, COPD35 and psoriasis.36
Beyond this classification, ILCs display plasticity and heterogeneity across tissues.37-39 ILCs are able to change their phenotype and function in response to changes in the local microenvironment, a characteristic which confounds attends to delineate and classify their role. In the presence of IL-12, ILC3s and ILC2s lose their RORγt and GATA-3 expression respectively, and can trans-differentiate into ILC1s expressing T-bet and producing IFN-γ.22, 40, 41 ILC1s can be reconverted into ILC3s by stimulation with IL-1β, IL-23 and retinoic acid.42Similarly, IL-1β and IL-4 can reconvert ILC1s into ILC2s.23