Introduction
The immune system is classically divided into two categories, innate and adaptive immunity, according to the speed and the duration of the response, and they collaborate with each other to target different agents and perform effector functions. Through recent advances in understanding the different subsets of immune system effector cells, Annunziato et al. have recently suggested a new classification [
1]. They proposed that the innate and adaptive immune systems could also be generally classified into three major kinds of cell-mediated effector immunity: categorized as type 1, comprising T-bet
+ IFN-γ–producing helper cells, type 2, composed of GATA-3
+ lymphocytes producing interleukin-4 (IL-4), IL-5, and IL-13, and type 3, characterized by RORγt
+ lymphocytes that produce IL-17 alone or in combination with IL-22 as signature cytokines [
1].
Innate immunity is known to respond quickly and without antigen specificity to signals derived from the environment or from other immune cells. Innate lymphoid cells (ILCs) are the newest described elements of the innate immune system and have received much attention over the last few years [
2]. Early in the immune response, ILCs possess a lymphoid morphology, similar to adaptive B and T cells, and produce many different T helper (T
H) cell cytokines but lack the recombination-activating gene (RAG)-mediated antigen specific receptors; therefore, these cells are not antigen-specific. Because ILCs are very similar to the other effector cell phenotypes, it was proposed that ILCs could be classified in a similar manner to that of T
H cells. Type 1 immunity includes the IFN-γ-producing group 1 ILCs (ILC1s) that cope with intracellular pathogens through activation of mononuclear phagocytes. Group 2 ILCs (ILC2s), which secrete IL-4, IL-5, IL-9, and IL-13, are an example of Type 2 immunity. This type of immunity induces mast cell, basophil, and eosinophil activation leading to an increase in serum IgE levels and, therefore, fosters the eradication of helminthes and venoms. Group 3 ILCs (ILC3s), which are an example of type 3 immunity, produce IL-17 and/or IL-22, activate mononuclear phagocytes, recruit neutrophils, and induce epithelial antimicrobial responses, all of which help protect against extracellular fungal and bacterial infections [
1]. This group includes lymphoid tissue inducer (LTi) cells that promote the formation of lymph nodes [
3].
In general, ILCs constitute a distinct element of the innate immune system, providing an initial host response via specific cytokines after sensing external stimuli on the frontline. The initial priming of immune responses to pathogenic challenges is executed by ILCs with the capacity to rapidly secrete effector cytokines. All ILCs are developmentally related, and they all require the expression of the transcriptional repressor inhibitor of DNA binding 2 (Id2) and the common IL-2 cytokine receptor (γ
c) chain. Moreover, they all possess the IL-7 receptor α-chain (CD-127) [
4].
The ILC lineage incorporates the classic cytotoxic natural killer (NK) cells and the non-cytotoxic ILC family [
5]. Natural killer cells are also capable of responding to invading pathogens and exterior threats without the need for prior sensitization, and they function in the absence of RAG-recombined antigen receptor recognition. Beside their ability to release a variety of cytokines, they also have the capacity to kill other cells. NK cells were initially categorized into ILC1s, but recently it has been shown that these cells are different from non-cytotoxic ILCs because they undergo different developmental pathways [
6,
7].
Non-cytotoxic ILCs have the capacity to rapidly respond to the environment by producing various cytokines, and their goal is to maintain homeostasis with tissue repair and remodeling. They are involved in lymphoid organ development and in resistance to pathogenic and nonpathogenic microorganisms. Non-cytotoxic ILCs also interact with mast cells, natural killer T (NKT) cells, eosinophils, epithelial cells, and macrophages, and they may configure the optimal milieu for setting up an adaptive response [
8,
5].
Asthma includes complex innate and adaptive immune responses to environmental factors. For decades, researchers investigating the immune responses in asthma have focused on adaptive immunity, mostly on memory responses to antigens. Therefore, asthma was previously considered to be the airway manifestation of a T
H2-driven response from adaptive immunity toward some specific triggers [
9]. Today, advances in molecular technology and recent immunology studies have allowed us to understand much more about the impact of the innate immune system on the development of asthma and on its evolution. Negative results from the initial monoclonal treatment drug studies and cluster analysis have demonstrated that “asthma syndrome” covers distinct subgroups of a reversible obstructive lung disease with different clinical properties termed different “phenotypes” [
10‐
12]. Although there is no consensus on a single phenotype classification for asthma, the most-studied subgroups include: T
H2-associated with early-onset allergic asthma, late-onset persistent eosinophilic asthma, virus-induced asthma, obesity-related asthma, and neutrophilic asthma. All of these subgroups can be distinguished from each other by clinical factors, such as the patient age at disease onset and the involvement of particular biological pathways.
Understanding new innate pathways will allow for more accurate asthma phenotyping and, subsequently, will help direct us to personalized care for our asthmatic patients. In this review, we provide an updated view on the emerging roles of non-cytotoxic ILCs in different asthma phenotypes.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
LPO drafted the manuscript. HM and MA reviewed and finalized the manuscript. All authors read and approved the final manuscript.