How are T(H)2-type immune responses initiated and amplified?

Abstract

CD4(+) T helper (T(H)) cells have crucial roles in orchestrating adaptive immune responses. T(H)2 cells control immunity to extracellular parasites and all forms of allergic inflammatory responses. Although we understand the initiation of the T(H)2-type response in tissue culture in great detail, much less is known about T(H)2 cell induction in vivo. Here we discuss the involvement of allergen- and parasite product-mediated activation of epithelial cells, basophils and dendritic cells and the functions of the cytokines interleukin-4 (IL-4), IL-25, IL-33 and thymic stromal lymphopoietin in the initiation and amplification of T(H)2-type immune responses in vivo.

Figure 1. T_H2 cell differentiation requires both GATA3 expression and STAT5 activation

GATA-binding protein 3 (GATA3) and activated signal transducer and activator of transcription 5 (STAT5) bind to crucial regulatory elements of the T helper 2 (T_H2) cytokine locus and are indispensable for interleukin-4 (IL-4) production and thus T_H2 cell differentiation. IL-2, IL-7 and thymic stromal lymphopoietin (TSLP) activate STAT5. Several pathways are involved in regulating GATA3 expression. IL-4, through the activation of STAT6, is important for GATA3 upregulation in vitro. Low signal strength T cell receptor (TCR) activation induces GATA3 expression in an IL-4- and STAT6-independent manner. Other signalling pathways, including the Notch and WNT pathways, have been reported to regulate Gata3 transcription, although whether their effect is direct is currently being investigated. γ_c, common cytokine receptor γ-chain; R, receptor.

Figure 2. Cytokines have crucial roles in the initiation and amplification of T_H2-type immune responses

Cysteine protease- and/or lipopolysaccharide (LPS)-containing allergens, as well as helminth products, can activate lung and intestinal epithelial cells to produce thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25) and IL-33, which initiate T helper 2 (T_H2)-type immune responses by acting on basophils, dendritic cells (DCs) and/or non-B non-T cells. The allergen Der p 2 is structurally homologous to MD2, a component of Toll-like receptor 4 (TLR4) signalling complex. A high dose of Der p 2 enhances allergic inflammation in a TLR4-dependent MD2-independent manner. Some cysteine proteases and helminth products, such as IL-4-inducing principle of Schistosoma mansoni eggs (IPSE), can also directly stimulate basophils to produce TSLP and IL-4. Omega-1, a component of S. mansoni egg antigen, modulates DC function to favour a T_H2 cell promoting phenotype. Basophils, DCs and possibly other cells can serve as antigen-presenting cells to drive T_H2 cell differentiation under the influence of various cytokines such as TSLP, IL-4 and IL-25. Cytokines produced by T_H2 cells, including IL-2, IL-4 and IL-25, can self-amplify the differentiation process. At the effector stage, T_H2 cells and epithelial cells may further amplify T_H2-type responses through a cytokine-mediated positive regulatory loop. Although they are not shown in the figure, other immune cells, including natural killer (NK) cells, NKT cells, γδ T cells, macrophages, B cells, eosinophils and mast cells, may also participate in the initiation and amplification of T_H2-type responses by creating a T_H2-biased cytokine environment. In addition, IL-4 may induce IL-12 production by DCs or kill T_H2-inducing DCs, suggesting there are also negative regulatory mechanisms for T_H2-type immune responses. PAR, protease-activated receptor; R, receptor; TCR, T cell receptor.

Figure 3. Basophils and dendritic cells, functioning as antigen-presenting cells, are differentially involved in various T_H2-type immune responses

Both basophils and dendritic cells (DCs) are involved in the fate determination of naive CD4⁺ T cells through cytokine production and antigen presentation; however, the relative importance of these two cell types seem to be different in various models. a | In papain-induced (and possibly other cysteine protease allergen-induced) T helper 2 (T_H2)-type responses, basophils seem to be crucial, whereas DCs are not essential. Interleukin-4 (IL-4) and thymic stromal lymphopoietin (TSLP), produced by activated basophils, are important for such T_H2 cell differentiation. b | Different Trichuris muris-derived products may simultaneously activate basophils and DCs. Basophils are predominantly involved in T_H2 cell induction, whereas DCs induce both T_H1 and T_H2 cell differentiation. TSLP produced by basophils may be required for suppressing IL-12 production by DCs, promoting the development of T_H2 cell-inducing DCs and inducing IL-4 production by T cells. IL-4 produced either by basophils or T cells is also crucial for inhibiting interferon-γ (IFNγ) production in T cells and amplifying T_H2-type responses. c | In some helminth infection models, helminth products including omega-1 can down-modulate the functions of activated DCs and suppress IL-12 production; therefore, IL-4-independent T_H2 cell differentiation occurs without the involvement of basophils. T_H2-type responses to Nippostrongylus brasiliensis do not require basophils, and such responses are both IL-4 and TSLP independent. PAR, protease-activated receptor; R, receptor; TCR, T cell receptor.