Orchestration between ILC2s and Th2 cells in shaping type 2 immune responses

Abstract

The type 2 immune response is critical for host defense against large parasites such as helminths. On the other hand, dysregulation of the type 2 immune response may cause immunopathological conditions, including asthma, atopic dermatitis, rhinitis, and anaphylaxis. Thus, a balanced type 2 immune response must be achieved to mount effective protection against invading pathogens while avoiding immunopathology. The classical model of type 2 immunity mainly involves the differentiation of type 2 T helper (Th2) cells and the production of distinct type 2 cytokines, including interleukin-4 (IL-4), IL-5, and IL-13. Group 2 innate lymphoid cells (ILC2s) were recently recognized as another important source of type 2 cytokines. Although eosinophils, mast cells, and basophils can also express type 2 cytokines and participate in type 2 immune responses to various degrees, the production of type 2 cytokines by the lymphoid lineages, Th2 cells, and ILC2s in particular is the central event during the type 2 immune response. In this review, we discuss recent advances in our understanding of how ILC2s and Th2 cells orchestrate type 2 immune responses through direct and indirect interactions.

Keywords: Allergy and asthma; Group 2 innate lymphoid cell (ILC2); Type 2 immune response; type 2 T helper cell (Th2).

Fig. 1

Classic model of a type 2 immune response. In allergic asthma or during helminth infection, an allergen or a helminthic antigen is phagocytosed by dendritic cells, which then migrate to the draining lymph node, where naïve CD4⁺ T cells recognize the processed antigen presented by the peptide-MHC-II complex along with costimulatory molecules. After recognition of antigen presented by dendritic cells (DCs), naïve CD4⁺ T cells differentiate into effector Th2 cells. Th2 cells migrate into the site of inflammation and produce Th2 cytokines such as IL-5, which is responsible for eosinophilia, and IL-13, which promotes mucus production and goblet cell hyperplasia. Th2 cells also produce IL-4, which is involved in antibody class switching and the production of IgE

Fig. 2

Type 2 immune response from the perspective of the ILC2-DC-Th2 cell-centric axis. Pathogen sensing or tissue damaging signals induced by exposure to helminth infection or protease allergen result in the secretion of alarmins, such as IL-25, IL-33, and TSLP. ATP released from epithelial cells may also induce mast cells to produce IL-33. These alarmin cytokines activate ILC2s, resulting in the production of the type 2 cytokines IL-4, IL-5, IL-9 and IL-13. The neuropeptide neuromedin U (NMU) can also activate ILC2s. The type 2 cytokines secreted by ILC2s may support the differentiation of naïve CD4 T cells into effector Th2 cells. Additionally, DCs receive signals from IL-13 secreted by ILC2s and TSLP released by epithelial cells during pathogen sensing and become capable of inducing effector Th2 cell differentiation from the naïve CD4 T cell population. IL-9 produced by ILC2s may act on these ILC2s to promote cell expansion as well as recruit mast cells. Overall, the type 2 cytokines secreted by ILC2s and Th2 cells, especially IL-5 and IL-13, cumulatively contribute to type 2 immunopathology

Fig. 3

ILC2s may play an important role in initiating a Th2 response. The pulmonary epithelial cells, which are primary sentinels of the lung, sense allergens and release alarmins, such as IL-33, IL-25 and TSLP, which activate ILC2s to produce IL-4, IL-5, IL-13 and amphiregulin (Areg). In turn, IL-5 and IL-13 induce eosinophilia, mucus production and goblet cell hyperplasia. Areg produced by ILC2s plays an important role in tissue repair. Activated ILC2s will initiate an adaptive effector Th2 response by either direct antigen presentation through cognate MHCII-TCR interactions along with costimulatory molecules or by secreting Th2-inducing cytokines such as IL-4. In some cases, the IL-13 secreted by ILC2s drives the activation of inactive CD11b⁺ DCs. The activated CD11b⁺ DCs migrate into the mediastinal lymph node, where naïve CD4 T cells differentiate into effector Th2 cells upon cognate MHCII-peptide-TCR interactions

Fig. 4

Direct interactions between ILC2s and CD4 T cells. CD4 T cells may directly interact with ILC2s through MHCII-peptide-TCR. ILC2s may also provide costimulatory signals to T cells through CD80, CD86, OX40L, and PD-L1. Additionally, it is possible that ILC2s induce naïve CD4 T cell differentiation into effector Th2 cells by secreting IL-4. Reciprocally, activated CD4 T cells may promote ILC2 expansion through IL-2 production

Fig. 5

Modulation of the type 2 immune response. Pulmonary epithelial cells sensing pathogen and allergen direct the development of ILC2s and Th2 cells. The IL-10 secreted by Tregs or Tr1 cells and TGF-β secreted by Tregs act at different stages of effector Th2 cell differentiation and control adaptive Th2 cell immunity. The functions of Tregs in regulating ILC2s are unknown. The release of IL-33 from epithelial cells, along with IL-2 secretion by mast cells as well as retinoic acid secretion by CD103⁺ DCs, creates a favorable environment for the generation of ILC2₁₀ cells. The IL-10 secreted from ILC2₁₀ cells may suppress ILC2 activation and thus control the immunopathology caused by other type 2 cytokines. The effect of ILCregs on ILC2s remains to be tested