Professional and 'Amateur' Antigen-Presenting Cells In Type 2 Immunity

Abstract

Dendritic cells (DCs) are critical for the activation of naïve CD4⁺ T cells and are considered professional antigen-presenting cells (APCs), as are macrophages and B cells. Recently, several innate type 2 immune cells, such as basophils, mast cells (MCs), eosinophils, and innate type 2 lymphocytes (ILC2), have also emerged as harboring APC behavior. Through surface expression or transfer of peptide-loaded MHCII, expression of costimulatory and co-inhibitory molecules, as well as the secretion of polarizing cytokines, these innate cells can extensively communicate with effector and regulatory CD4⁺ T cells. An exciting new concept is that the complementary tasks of these 'amateur' APCs contribute to shaping and regulating adaptive immunity to allergens and helminths, often in collaboration with professional APCs.

Keywords: antigen presentation; antigen-presenting cells; basophils; innate lymphoid cells; mast cells; type-2 immunity.

Figure 1

Allergen Presentation Leading to a Primary T helper Type 2 (Th2) Response in Mice and Humans. When inhaled allergens (Ag) reach the deeper parts of the lungs upon first antigen encounter (left), they can be taken up by conventional dendritic cells (cDCs) probing the mucosa, or by alveolar macrophages scavenging the allergen for destruction. Allergens are often good at eliciting a type 2 innate immune responses in barrier epithelial cells producing interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP). These cytokines instruct cDC2s to become inducers of Th2 polarization (often suppressing IL-12 and inducing OX40L, not depicted). The same epithelial cytokines also boost the innate functions of type 2 innate lymphocytes (ILC2) and resident Th2 cells [in the absence of cognate MHC-T cell receptor (TCR) interactions], boosting DC migration via secretion of IL-13; mast cells (MCs) boost DC migration via the secretion of TNFα. cDC2s migrate via the afferent lymphatics to the draining nodes and interact with naïve T cells that extravasate from high endothelial venules (HEV). cDC2s induce clonal selection, arrest, and proliferation of antigen-reactive T cells. Some of these primed T cells also interact with B cells by presenting their cognate antigen, eliciting help via B cell immunoglobulin E (IgE) class switching, and promoting their differentiation into IL-4-producing T follicular helper cells (T_FH). The precise source of polarizing IL-4 for Th2 differentiation is a matter of intense debate. It could derive from basophils, acquiring MHCII from DCs via trogocytosis, and interacting with T cells via peptide-MHCII complexes, while also releasing IL-4. Eosinophils also have an accessible IL4 locus, and can also interact with primed T cells in draining lymph nodes. It is unclear whether these eosinophils might communicate with naïve T cells or with recirculating T central memory (T_CM) cells. The source of IL-4 might also be the naïve T cells themselves, producing IL-4 when DCs generate IL-12 and express surface molecules, such as OX40-L and Notch ligands.

Figure 2

Antigen Presentation during Ongoing T Helper Type 2 (Th2) Immunity in Mice and Humans. Upon repeated or ongoing contact with allergens, T cells that have been primed during the primary phase of the immune response now extravasate into tissues, facilitated by signals from basophils (BA) and other innate immune cells priming the vessel wall via interleukin (IL)-4 and/or IL-13. Tissue-resident memory T cells (T_RM) are sessile in tissues. These T_EFF cells are restimulated primarily by CD11b+ CD172+ type 2 conventional dendritic cells (cDC2s) and monocyte-derived DCs (moDCs) harboring a non-migratory behavior (e.g., similar to macrophages). The precise nature of the antigen-presenting cell (APC) that presents antigen to T_RM cells remains unknown. At this stage of the response, moDCs are also armed with Fc receptors for immunoglobulin (Ig)-E and IgG so that allergens are better recognized. The interstitial macrophages still act to suppress the response, either by scavenging the allergen or by boosting the formation of regulatory T cells (Tregs). Accumulating evidence suggests that, in sites of ongoing type 2 immunity, many type 2 innate immune cells, such as innate type 2 lymphocytes (ILC2s), basophils, and eosinophils (EO), express MHCII, potentially leading to direct antigen presentation to Th2 cells. This could elicit help from Th2 cells for innate functions or the process might help Th2 cells to survive or modulate their function. As an eventual outcome, Th2 effector cells and innate immune cells produce massive amounts of IL-4, IL-5, and IL-13, controlling many of the features of allergic airway inflammation, such as goblet cell metaplasia, tissue eosinophilia, and bronchial hyper-reactivity.