Antigen‐Presenting Cells

Abstract

Professional antigen‐presenting cells (APCs) comprise dendritic cells (DCs), macrophages (MΦs) and B cells. Collectively, they initiate an adaptive immune response to pathogens, shape the nature of this response and contribute to its regulation and termination. They also play key roles in maintenance of tolerance to self‐antigens. Only DCs are able to activate naïve T cells, and from this pivotal position at the initiation of a response, they are able to shape the differentiation of the T cells towards different functional fates and instruct trafficking of these cells to sites of infection. In contrast, MΦs and B cells re‐stimulate T cells, previously activated by DCs in an antigen‐specific manner. They function to amplify the initial DC‐activated response and to elicit the targeted production of T cell‐derived factors required for antibody production by B cells and the enhanced microbicidal activity of MΦs.

Key Concepts

  • Cells that express MHC class II under resting conditions are often termed ‘professional’ antigen‐presenting cells (APCs).
  • Professional APCs comprise dendritic cells (DCs), macrophages (MΦs) and B cells.
  • Many tissue MΦs are derived from embryonic precursors and locally renew; DCs, B cells and some MΦs are derived by distinct pathways, in adult bone marrow.
  • Only DCs can activate naïve T cells.
  • DC‐derived signals shape the differentiation of CD4 T cells towards different functional subsets and can influence the trafficking of the cells generated to different tissues.
  • DCs can also induce tolerance via deletion, anergy and generation of T cells with regulatory properties.
  • Small numbers of DCs carrying self‐antigens constitutively migrate to secondary lymphoid organs (SLOs), but in the absence of exposure to infection‐associated ‘danger’ signals they express low levels of co‐stimulatory molecules and fail to stimulate adaptive immunity.
  • In infection, DCs undergo maturation in response to danger signals; mature DCs presenting foreign antigens and expressing high levels of co‐stimulatory molecules induce effector T cell responses.
  • B cells present antigen to DC‐activated T cells in order to trigger the targeted release of T cell derived factors that are required by B cells for production of high‐quality antibodies (‘T cell help’).
  • MΦs present antigen to DC‐activated T cells in order to trigger the targeted release of cytokines that activate the MΦ for enhanced microbicidal activity, reducing collateral tissue damage caused by toxic metabolites involved in pathogen killing.

Keywords: dendritic cells; macrophages; B cells; MHC; antigen processing; antigen presentation; co‐stimulation; tolerance; T cell differentiation; T cell trafficking

Figure 1. An overview of the development of major types of antigen‐presenting cells (APCs). Macrophages (MΦs) resident in adult tissues can be derived from either embryonic progenitors or from monocytes generated by haematopoiesis in the adult bone marrow. B cells are derived in the bone marrow from a committed lymphoid progenitor. They egress as immature B cells (Imm B cell) and complete their development in peripheral lymphoid tissues. All three major DC subsets (cDC1, cDC2 and pDC) are derived from a common progenitor that has lost monocyte potential. Although DCs are not derived from monocytes in the steady‐state, monocytes can differentiate to yield cells with some properties of DCs under inflammatory conditions (inflammatory DCs). Key transcription factors and cytokines are shown in italics and boxes, respectively. Dotted lines represent alternative or unconfirmed pathways of development. EMP, erythro‐myeloid precursors; HSC, haematopoietic stem cell; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; MDP, monocyte DC progenitor; CDP, common DC progenitor; cMoP, common monocyte precursor.
Figure 2. DC maturation and the expression of co‐stimulatory molecules is required to generate effector T cell responses. Bone marrow‐derived pre‐cDCs give rise to immature cDCs in most tissues of the body. These immature cDCs constitutively traffic, bearing self‐antigens, to draining SLOs where encounter with any potentially autoreactive T cell leads to induction of anergy or induction of Tregs as the result of low co‐stimulatory molecule expression. In infection, danger signals sensed by TLRs and other PRRs, result in DC maturation characterised by increased expression of costimulatory molecules. Trafficking of mature cDCs to SLOs is enhanced due to increased CCR7 expression and results in the activation of pathogen‐specific T cells due to the ability of mature DCs to provide co‐stimulation. CD4 T cells can differentiate to generate a variety of effector cells (Th1, Th2, etc.) or regulatory populations; these fates can be influenced by cDC‐derived cytokines and other signals. Other environmental cues act on the DC, or on the T cell during activation, to influence the balance of these T cell fates.
Figure 3. T cells activated by DCs in SLOs traffic selectively back to the site of infection where further interactions with APCs occur. Intestinal DCs have the ability to generate the vitamin A metabolite all‐trans retinoic acid (RA). Exposure of T cells to RA during their activation by intestinal DCs results in their expression of the integrin α4β7 and the chemokine receptor CCR9. These two molecules act together to target the T cells back to the intestinal mucosa; α4β7 binds to MAdCAM‐1, an address in expressed selectively on vascular endothelium in the intestine and CCL25, the ligand for CCR9 is expressed in the small intestine in particular (boxed diagram). Binding of CCL25 to CCR9 enhances the α4β7‐MAdCAM‐1 interaction, enabling T cell extravasation at this site. Within the mucosa, the recruited T cells are able to interact with further specialised intestinal APC populations to further shape their activity and contribute to the tightly regulated intestinal immune response.
Figure 4. The role of different APC populations. Only DCs are capable of activating naïve T cells to stimulate the clonal expansion and differentiation of antigen‐specific cells to yield functionally committed subsets. The T cells generated in this way (e.g. Th1, Th2, Th17, TFH cells) can be reactivated subsequently by the same antigen presented on the surface of B cells and MΦs, as well as DCs. Presentation by B cells elicits the production of T cell‐derived factors required for production of high affinity antibody (T cell help). Presentation by MΦs elicits T cell cytokines that enhance their capacity to kill microbes (MΦ activation). These pathways provide important checkpoints and ensure T cell‐derived signals are focussed on relevant cells.
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Stagg, Andrew J, Hornsby, Eve, and Knight, Stella C(Aug 2020) Antigen‐Presenting Cells. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0029138]