Insights into the initiation of type 2 immune responses

Abstract

Type 2 immune responses, characterized by the differentiation of CD4+ T helper type 2 (Th2) cells and the production of the type 2 cytokines interleukin-4 (IL-4), IL-5, IL-9 and IL-13, are associated with parasitic helminth infections and inflammatory conditions such as asthma and allergies. Until recently the initiating factors associated with type 2 responses had been poorly understood. This review addresses the recent advances in identifying the diverse range of antigens/allergens associated with type 2 responses and the function, expression and sources of type-2-initiating cytokines (thymic stromal lymphopoietin, IL-25 and IL-33). We also discuss the latest findings regarding innate lymphoid cells, such as nuocytes, as early sources of type 2 cytokines and their importance in protective immunity to helminth infections. These developments represent major breakthroughs in our understanding of type 2 immunity, and highlight the increased complexity existing between the innate and adaptive arms of these responses. These additional steps in the type 2 immune pathway also offer potential targets for therapeutic intervention.

Figure 1

Expression and function of type 2 effector cytokines. Type 2 effector cytokines come from a variety of sources including antigen-stimulated CD4⁺ T-cell subsets such as T helper type 2 (Th2) and Th9 cells, antigen-stimulated basophils or cytokine-stimulated innate lymphoid cells (ILC), such as nuocytes. It is the expression of these cytokines that leads to IgE class switching, goblet cell hyperplasia, which is important for mucus production, recruitment of various innate cell populations like eosinophils, basophils and mast cells, and enhanced the proliferation and differentiation of CD4⁺ T cells. IL-4, interleukin-4.

Figure 2

A complex cytokine network underlies the initiation of type 2 immune responses. Antigen stimulation, leads to thymic stromal lymphopoietin (TSLP) or interleukin-25 (IL-25) expression from non-haematopoietic cell sources that subsequently induce type 2 effector cytokine expression from various cell populations including innate lymphoid cells, basophils or CD4⁺ T cells. Alternatively, IL-33, which induces many of the features similar to IL-25 and TSLP, is released as an active form from necrotic cells and acts as an alarmin. In addition, certain antigens such as Omega-1 from Schistosoma mansoni condition dendritic cells (DCs) so that they guide CD4⁺ T cells towards a type 2 response. IPSE, inducing principle of Schistosoma mansoni; Th2, T helper type 2; TLR4, Toll-like receptor 4.