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