The realization that various cells other than T cells are needed to present antigens to T lymphocytes first came from studies in which protein antigens that were known to elicit T-cell responses were labeled and injected into mice, to determine which cells bound (and, by implication, recognized) these antigens. The result was that the injected antigens were associated mainly with nonlymphoid cells, which was a surprise because it was known that lymphocytes were the cells that specifically recognized and responded to foreign antigens. This type of experiment was soon followed by studies showing that protein antigens that were physically associated with myeloid cells (e.g., macrophages) were much more immunogenic, on a molar basis, than the same antigens injected into mice in soluble form. Subsequent cell culture experiments showed that purified CD4+ T cells could not respond to protein antigens, but they responded very well if non–T cells such as dendritic cells (DCs) or macrophages were added to the cultures. These results led to the concept that an essential step in the induction of a T-cell response is the presentation of the antigen to T lymphocytes by other cells, which were named APCs. The first APCs identified were macrophages, and the responding T cells were CD4+ helper cells. It soon became clear that several cell populations can function as APCs in different situations. By convention, APC is still the term used to refer to specialized cells that display antigens to CD4+ T lymphocytes. As we will see later in this chapter, all nucleated cells can display peptide antigens to and activate CD8+ effector T lymphocytes, but they are not all called APCs.

General Properties of Antigen-Presenting Cells

Different cell types function as APCs to activate naive T cells or previously differentiated effector T cells (Fig. 1 and Table 1). DCs are the only cell type capable of capturing antigens and migrating to secondary lymphoid organs and are, therefore, the most effective APCs for activating naive T cells and for initiating T-cell responses. Macrophages and B lymphocytes also function as APCs, but mostly for previously activated CD4+ helper T cells rather than for naive T cells. Their roles as APCs are described later in this chapter and in more detail in Chapters 10 and 12. DCs, macrophages, and B lymphocytes express MHC-II molecules and are therefore capable of activating CD4+ T lymphocytes. For this reason, these three cell types have been called professional APCs; however, this term is sometimes used to refer only to DCs because of their unique role in naive T-cell activation.

Fig1. Functions of different antigen-presenting cells. The three major types of antigen-presenting cells for CD4+ T lymphocytes function to display antigens at different stages and in different types of immune responses. Note that effector T cells activate macrophages and B lymphocytes by production of cytokines and by expressing surface molecules; these will be described in later chapters. Dendritic cells also present antigen to naive CD8+ T cells (not shown), and all nucleated cells can present antigen to CD8+ effector T cells, which respond by killing the antigen-producing cells (not shown).

APCs display peptide-MHC complexes for recognition by T cells and also provide additional stimuli that are required for the full responses of the T cells. Antigen, which is peptide bound to an MHC molecule, provides the first signal to T cells through the TCR, and the additional stimuli that are required for T cell activation are sometimes called second signals. These second signals are more important for the activation of naive T cells than for the restimulation of previously activated effector and memory cells. The membrane-bound molecules of APCs that function together with antigens to stimulate T cells are called costimulators. APCs also secrete cytokines that play critical roles in the differentiation of naive T cells into effector cells.

The antigen-presenting function of APCs is enhanced by expo sure to microbial products. This is one reason that the immune system responds better to microbes than to harmless, nonmicrobial substances. DCs and macrophages express Toll-like receptors and other innate immune microbial sensors and respond to microbes by increasing the expression of MHC molecules and costimulators, by improving the efficiency of antigen processing to generate peptides that bind to MHC molecules, and by activating the APCs to produce cytokines, all of which help stimulate T-cell responses. In addition, DCs that are activated by microbes express chemokine receptors that facilitate their migration to sites where naive T cells are present.

APCs that present antigens to T cells also receive signals back from these lymphocytes that enhance the antigen- presenting function of the APCs. In particular, CD4+ T cells that are activated by antigen recognition and costimulation express surface molecules, notably one called CD40 ligand (CD154), which binds to CD40 on DCs and macrophages, and the T cells also secrete cytokines, such as interferon-γ (IFN-γ), that bind to their receptors on these APCs. The combination of CD40 signals and cytokines activates the APCs, resulting in increased ability to process and present antigens, increased expression of costimulators, and secretion of cytokines that activate the T cells. This bidirectional interaction between APCs displaying the antigen and T lymphocytes that recognize the antigen functions as a positive feedback loop that plays an important role in maximizing the immune response.

Role of Dendritic Cells in Antigen Capture and Display

 Microbes and protein antigens that enter through epithelia are concentrated in lymph nodes, and blood-borne antigens are captured mostly in the spleen (Fig. 2). The common routes through which foreign antigens, such as microbes, enter a host are the skin and the epithelia of the gastrointestinal and respiratory systems. In addition, microbial antigens may be produced in tissues that have been colonized by microbes. The skin, mucosal epithelia, and parenchymal organs contain numerous lymphatic capillaries that drain lymph from these sites and into the regional lymph node. Some antigens are transported in the lymph by APCs (primarily DCs) that capture the antigen and enter lymphatic vessels, and other antigens enter the lymphatics in cell-free form. Thus, the lymph contains a sampling of all the soluble and cell-associated antigens that enter through epithelia and are present in tissues. The antigens become concentrated in lymph nodes into which the lymph flows. Lymph nodes are interposed along lymphatic vessels and act as filters that sample the lymph before it reaches the blood. Antigens that enter the bloodstream may be sampled by APCs that are resident in the spleen, which has a rich blood supply.

Fig2. Routes of antigen entry. Microbial antigens commonly enter through the skin and gastrointestinal and respiratory tracts, where they are captured by dendritic cells and transported to regional lymph nodes. Antigens that enter the bloodstream are captured by antigen-presenting cells in the spleen.

DCs were introduced in Chapter 2, and their functions as tissue-resident sentinels that recognize microbes and trigger innate immune reactions were discussed in Chapter 4. Here we describe the role of these cells in antigen presentation to T lymphocytes.

DCs that are resident in epithelia and tissues capture protein antigens. Tissue-resident conventional DCs (cDCs) express numerous membrane receptors, such as C-type lectins, that bind microbes. DCs use these receptors to capture and endocytose microbes or microbial proteins and then process the ingested proteins into peptides capable of binding to MHC molecules. In addition to receptor-mediated endocytosis and phagocytosis, DCs can ingest antigens by pinocytosis, a process that does not involve specific receptors but serves to internalize whatever molecules might be in the fluid phase in the vicinity of the DCs.

Simultaneously with antigen capture, DCs are activated by microbial products to mature into APCs that transport the captured antigens to draining lymph nodes (Fig.3). At the time that microbial antigens are being captured, microbial products (i.e., pathogen-associated molecular patterns [PAMPs]), different from the protein antigens that T cells recognize, are recognized by Toll-like receptors and other innate pattern recognition receptors in the DCs and other cells, generating innate immune responses. The DCs are activated by these signals and by cytokines, such as tumor necrosis factor (TNF), produced in response to the microbes. The activated DCs (also called mature DCs) lose their adhesiveness for epithelia or connective tissue and begin to express a chemokine receptor called CCR7 that is specific for two chemokines, CCL19 and CCL21, which are produced in lymphatic vessels and in the T-cell zones of lymph nodes. These chemokines attract the DCs bearing microbial antigens into draining lymphatics and ultimately into the T-cell zones of the regional lymph nodes. Naive T cells also express CCR7, and this is why they localize to the same regions of lymph nodes where antigen-bearing DCs are concentrated, although their route into the lymph node is via the blood. The colocalization of antigen-bearing activated DCs and naive T cells maximizes the chance of T cells with receptors for the antigen finding the antigen they can recognize.

Fig3. Role of dendritic cells (DCs) in antigen capture and presentation. (A) Immature DCs in the skin (Langerhans cells) or dermis capture antigens that enter through the epidermis and transport the antigens to regional lymph nodes. During this migration, the DCs mature and become efficient antigen-presenting cells. (B) The table summarizes some of the changes during DC maturation that are important in the functions of these cells. Half-life is an estimate of how long the molecules are expressed on cells. The number of surface molecules is per class II–expressing cell. ICAM-1, Intercellular adhesion molecule 1; IL-12, interleukin-12; MHC, major histocompatibility complex.

Activation also converts the DCs from cells whose primary function is to capture antigen into cells that are able to present antigens to naive T cells and to activate the lymphocytes. Activated DCs express high levels of MHC molecules with bound peptides and costimulators required for T-cell activation. Thus, by the time these cells arrive in the lymph nodes, they have developed into potent APCs with the ability to activate T lymphocytes. Naive T cells that recirculate through lymph nodes encounter these APCs, and the T cells that are specific for the displayed peptide-MHC complexes are activated. This is the initial step in the induction of T-cell responses to protein antigens.

In the absence of infection or inflammation, conventional DCs capture antigens in the tissues but few migrate to lymph nodes and they are not activated to produce the high levels of cytokines and costimulators that are required to induce effective immune responses. The function of these DCs may be to present self antigens to self-reactive T cells and thereby cause inactivation or death of the T cells or generate regulatory T cells. These mechanisms play a role in maintaining self-tolerance and preventing autoimmunity.

Antigens are also transported to lymphoid organs in soluble form. Resident DCs in the lymph nodes and spleen may capture lymph- and blood-borne antigens, respectively, and also may be driven to mature by microbial products. When lymph enters a lymph node through an afferent lymphatic vessel, it drains into the subcapsular sinus, and some of the lymph enters fibroblast reticular cell (FRC) conduits that originate from the sinus and traverse the cortex. Once in the conduits, low molecular-weight antigens can be extracted by DCs that line the outside surfaces of the conduits and whose processes interdigitate between the FRCs. Other antigens in the subcapsular sinus are taken up by macrophages, which carry the antigens into follicles and present these antigens to resident B cells. B cells in the node may also recognize and internalize soluble antigens.

The collection and concentration of foreign antigens in lymph nodes are supplemented by other anatomic adaptations that serve similar functions. The mucosal surfaces of the GI and respiratory systems, in addition to being drained by lymphatic capillaries, contain specialized collections of secondary lymphoid tissue that can directly sample the luminal contents of these organs for the presence of antigenic material. The best characterized of these mucosal lymphoid organs are Peyer’s patches of the ileum and the pharyngeal tonsils. APCs in the spleen monitor the bloodstream for any anti gens that reach the circulation. Such antigens may reach the blood either directly from the tissues or by way of the lymph from the thoracic and right lymphatic ducts.

Several properties of conventional DCs make them the most efficient APCs for initiating primary T-cell responses.

• DCs are strategically located at the common sites of entry of microbes and foreign antigens (in epithelia) and in tissues that may be colonized by microbes.

• DCs express receptors that enable them to capture and respond to microbes.

 • In response to chemokines, activated DCs migrate from epithelia and tissues via lymphatics, preferentially into the T-cell zones of lymph nodes, the same regions of the lymph nodes through which naive T lymphocytes also circulate.

• Mature DCs express high levels of peptide-MHC complexes, costimulators, and cytokines, all of which are needed to activate naive T lymphocytes.

• Specialized DCs (cDC1) can transfer internalized proteins from phagosomes into the cytosol and are thus efficient at cross-presenting antigens to CD8+ T cells. As we will see later, this process is essential for initiating CD8+ T-cell responses to many viruses and tumors.

Functions of Other Antigen-Presenting Cells

Although DCs have a critical role in initiating primary T-cell responses, other cell types are also important APCs in different situations (see Fig. 1 and Table 1).

• In cell-mediated immune responses, macrophages present the antigens of phagocytosed microbes to effector T cells, which respond by activating the macrophages to kill the ingested microbes. This process is central to cell-mediated immunity. Circulating monocytes are able to migrate to any site of infection and inflammation, where they differentiate into macrophages and phagocytose microbes as a prelude to destruction. Tissue-resident macro phages may serve the same functions. CD4+ T cells recognize microbial antigens being presented by the macrophages and provide signals that enhance the microbicidal activities of these macrophages. The requirement for specific antigen recognition means that T cells mainly activate the macrophages containing the microbe that is the source of the antigen.

• In humoral immune responses, B lymphocytes internalize protein antigens and present peptides derived from these proteins to helper T cells. This antigen-presenting function of B cells is essential for helper T cell–dependent antibody production.

 • All nucleated cells can present peptides, derived from cytosolic protein antigens, to CD8+ CTLs. All nucleated cells are susceptible to viral infections and cancer-causing mutations. Therefore, it is important that the immune system be able to recognize cytosolic antigens, such as viral antigens and mutated proteins, in any cell type. CD8+ CTLs are the cell population that recognizes these antigens and eliminates the cells in which the antigens are produced. CD8+ CTLs may also recognize phagocytosed microbes if these microbes or their antigens are transported from phagocytic vesicles into the cytosol.

• Other cell types that express MHC-II molecules and may present antigens to CD4+ T cells include endothelial and some epithelial cells. Vascular endothelial cells may present antigens to blood T cells that adhere to vessel walls, but the role of this process in cell-mediated immune reactions is unclear. Endothelial cells in grafts also are targets of T cells reacting against graft antigens. Various epithelial and mesenchymal cells may express MHC-II molecules in response to the cytokine IFN-γ. The physiologic significance of antigen presentation by these cell populations is not established. Because most of them do not express costimulators and are not efficient at processing proteins into MHC-binding peptides, it is unlikely that they contribute significantly to the majority of T-cell responses. Thymic epithelial cells constitutively express both MHC-I and MHC-II molecules and play a critical role in presenting peptide MHC complexes to maturing T cells in the thymus as part of the selection processes that shape the repertoire of T-cell specificities.

اخر الاخبار

اخبار العتبة العباسية المقدسة

شعبة التوجيه الديني النسوي تنظم مسابقة ثقافية بذكرى ولادة السيدة المعصومة (عليها السلام)

المجمع العلمي ينظّم محاضرةً تربوية لطلبة مشروع حفظ القرآن الكريم في كربلاء

قسم الشؤون الفكرية يقيم معرضًا وثائقيًا ضمن مهرجان (الشهيد) في جامعة الكوفة

قسم الشؤون الدينية يشهد إقبالًا واسعًا من المؤمنين لتنظيم عقود الزواج

المزيد

الآخبار الصحية

عدد مرات التبرز يكشف أسرارا عن صحة الأمعاء

علامات جينية طويلة الأمد تتركها الرضاعة الطبيعية في دم الطفل

هل يمكن إعادة برمجة الجهاز المناعي لإنتاج أجسام مضادة نادرة؟

دراسة: أدوية الزهايمر "لا تحدث فرقا يذكر لدى المرضى"

المزيد

الآخبار التكنلوجية

روسيا تطور تقنية جديدة لتعديل خصائص البلاديوم

الصين: طاقم مهمة شينتشو-21 سيبقى في الفضاء شهرا آخر

"أوبن إيه آي" تكشف "جي بي تي-5.4-سايبر"

"أبل" تهدد بحذف تطبيق "غروك" من متجرها وتكشف السبب

المزيد

مواضيع ذات صلة

Cytosolic DNA Sensors and the STING Pathway

RIG-Like Receptors

Inflammasomes

Antigens

NOD-Like Receptors: NOD1 and NOD2

Recognition of Microbes and Damaged Tissue by the Innate Immune System

Overview of Innate Immunity

Transplantation of Tissues and Organs

Rh Blood Types

O-A-B Blood Types

Allergy and Hypersensitivity

The Antiviral Response