Type 2 Innate Lymphoid Cells: Friends or Foes—Role in Airway Allergic Inflammation and Asthma

Table 2

Innate lymphoid cells (ILCs) family^a,b.

Cell type	Date of discovery; and naming in the first publish	Anatomical; locations	Major stimulating; and development-effective; cytokines	Major transcription; factors and molecules; needed for development	Major cytokines; produced by cells	Major; surface; markers	Major functions; and pathology	Reference
NK cells; (cytotoxic ILCs)	(i) Kiessling et al. 1975; [29]; (ii) Herberman et al. 1975; [30]	(i) Secondary lymphoid tissues; (ii) Blood; (iii) Mucosal tissues; (iv) BM and thymus (less common)	(i) IL-12, IL-15, IL-18; (ii) IL-2, IL-21	Id2; Tox; T-bet; E4BP4; Eomes	IFN-𝛾; IL-3; IL-10; TNF-α; G-CSF; GM-CSF; CCL2; CCL3; CCL4; CCL5; XCL-1; IL-8	(i) Cytokine receptors^1; (ii) Chemokine receptors^2; (iii) Adhesion molecules^3; (iv) Activating receptors^4; (v) Inhibitory receptors^5	(i) Innate responses against viral infections; (ii) Immune surveillance against tumors	[29–35]
Rorγt^+ ILCs	First subset: Mebius et al. 1997 [36]	(i) Fetal lymphoid organs; (ii) Tonsils, intestines, spleen, Peyer’ patches	(i) IL-1β, IL-23; (ii) IL-7	Ror𝛾t; Id2; Tox; AhR; Notch2 (just in adults)	IL-17; IL-22; IL-2; IL-13; GM-CSF; TNF-α; LT; CXCL-18	(i) In all subsets: CD127 (IL-7Rα), CD161, CD117 (c-kit), OX40L, CD30L; (ii) In some subsets: CD4, CD90, CD56, NKP44 ( in human), NKP46 (in mouse), RANK, RANKL	(i) Lymphoid tissue formation (organogenesis); (ii) Tissue repair; (iii) Innate immunity against bacterial and yeast infections; (iv) Triggering of IgA production independently from T cells; (v) Mucosal immunity^6; (vi) Mucosal homeostasis^7; (vii) Intestine and cancer pathology^8	[2, 36–39]
Type 2 ILCs (ILCs2)	2001, 2002,; 2010, 2011; (more detail in Table 3)	(i) FALC; (ii) Lungs and gut; (iii) mLN; (iv) Palatine tonsils; (v) Spleen; (vi) Liver; (viii) Peripheral blood	(i) IL-25, IL-33; (ii) IL-7	Id2	IL-5; IL-13	(i) In human: CRTH2 (GPR44), IL-7R𝛼, IL-7RB, CD25, ST2; (ii) In mouse: CD44, Thy1, c-kit	(i) Helminth expulsion; (ii) Tissue homeostasis; (iii) Airway inflammation and remodeling	[2]

^aThe biology and functions of NK cells and Rorγt⁺ ILCs are in more details than ILC 2. The latter cells are our target cells in this paper so we meet them in great details through the text. ^bEach three major cell types of ILC family are actually a heterogeneous population so in this table just common features of subsets of each subfamily have been indicated.
¹IL-1R, IL-2R, IL-12R, IL-15R, IL-18R, IFN-α. ²CCR2, CCR5, CCR7, CXCR1, CXCR3, CXCR4, CXCR6,CX3CR1, S1P5, Chem23R. ³CD2, CD56, CD122, DX5, CD11b, DNA M1, β1-integrins, β2-integrins. ⁴NKPs (NCRs), CD16, NKG2D, NKR-P1C, KIR-S, CD94/NKG2C, CRACC, ly9, CD84, NTB4, 2B4. ⁵LAIR1, KLRG1, NKR-P1B, NKR-P1D, TIGIT, CEACAM1, KIR-L, LILRB1, ly49, CD94/NKG2A.
⁶For example, by interaction with T cell, through CD30L and OX40L, that causes survival of Th2 and memory T cells. ⁷For example, by TNF-α-dependent activation of matrix metalloproteinases that lead to TGF-β production and in return IgA secretion by B cells. ⁸In intestine pathology, for example, by by IL-17 production and in return promotion and aggravation of mucosal inflammation. In cancer pathology, for example, by tumor expansion through recalling and recruitment immune suppressive cells.
Ror𝛾t: transcription factor retinoic acid (RA) receptor-related orphan receptor (Ror) 𝛾t, Tox: thymocyte selection-associated high-mobility group box protein, Eomes: eomesodermin, T-bet (Tbx21): T-box transcription factor expressed in T cells, E4BP4 (NFIL3): nuclear factor IL-3 regulated (a basic leucine zipper transcription factor), AhR: aryl hydrocarbon receptor, LT: lymphotoxin, FALC: fat-associated lymphoid cluster, mLN: mesenteric lymph nodes, BM: bone marrow.