Antigen-presenting cells

INTRODUCTION — The mechanism by which an antigen triggers an adaptive immune response involves several steps. Potentially antigenic particles must be captured, processed, and presented in recognizable form to T cells with the appropriate concomitant signals. The cells that perform these functions are antigen-presenting cells (APCs). The antigen processing and T cell priming functions of APCs, as well as clinical implications and applications of these cells, are presented in this topic review. The cellular interactions that form the basis of the cellular immune response and an overview of major histocompatibility complex (MHC) structure and function are presented separately. (See "The adaptive cellular immune response: T cells and cytokines" and "Major histocompatibility complex (MHC) structure and function".)

PROFESSIONAL APCs — Most nucleated cells express at least some of the major histocompatibility complex (MHC) proteins required to present antigens to T cells, a feature that endows all cells with the potential to become targets of the immune response when damaged or infected. However, only a selected subset of hematopoietic lineage cells possesses the specialized machinery required to efficiently activate or "prime" naïve T cells and thereby initiate a new adaptive immune response. These cells are "professional" APCs.

There are three professional APCs:

●Macrophages

●Dendritic cells (DCs)

●B lymphocytes

MAJOR FUNCTIONS — APCs perform four major functions:

●They constantly sample the environment, both intracellular and extracellular, for potentially antigenic molecules.

●They contain specialized intracellular machinery to break down these molecules and particles and present components of them on the cell surface in a form recognizable to T lymphocytes.

●They shuttle antigens from tissues to the sites of lymphocyte priming, which are the peripheral lymphoid organs (ie, lymph nodes, Peyer patches in the intestinal wall, tonsils and adenoids, appendix, and spleen).

●They provide critical accessory signals, without which T cells cannot become fully activated.

Monitoring the intracellular environment — Antigen processing and presentation are occurring continually in most normal cells of the body. As old or malfunctioning biomolecules are recycled through specific cellular pathways, an everchanging pool of molecular fragments is generated. If the cell is infected by a pathogen that replicates within the cell cytoplasm, the foreign proteins of the invader are dealt with and presented along the same pathways that process self-proteins. Thus, self-peptides are constantly presented alongside non-self-peptides. The ability of T cells to discriminate between the two is not intrinsic to the T cell itself but rather is enforced through a complex network of regulatory mechanisms that are active from the earliest stages of thymocyte development. These mechanisms are discussed separately. (See "Overview of autoimmunity", section on 'Pathogenetic mechanisms'.)

The processing and presentation of intracellular antigens is principally major histocompatibility complex (MHC) I restricted (figure 1). MHC I molecules are expressed by most nucleated cells, although professional APCs express significantly higher levels of MHC I. The antigenic peptide:MHC I complexes assembled in the endoplasmic reticulum (ER) are the priming ligands for CD8+ (cytotoxic) T cell responses. Recognition of the T cell by these complexes under appropriate conditions leads to the destruction of cells harboring intracellular infectious agents.

Antigens from viruses and other pathogens that replicate within the host cell cytoplasm, such as the bacterium Listeria, can also be shed from the cell. Under these conditions, the antigens may be taken up as particles or whole damaged cells may be phagocytosed and the antigens then processed by the MHC II pathway. This pathway is important for inducing CD4+ T cell responses to antigens from intracellular pathogens.

Antigen acquisition — The MHC I antigen-processing pathway begins with cellular proteins that are misfolded, damaged, or targeted by regulatory mechanisms for destruction. During the course of intracellular viral or bacterial replication, proteins of microbial origin are also processed through this pathway. These proteins are degraded by the proteasome, a large, barrel-shaped, multicatalytic protease found within the cytosol.

The peptide products released from the proteasome exhibit extensive heterogeneity, and only a small fraction of these peptides will bind to MHC I molecules. A highly specialized heterodimeric protein in the ER membrane, termed the "TAP complex" (for transporter associated with antigen processing), imports a subset of these peptide products from the cytosol into the ER lumen. Inside the ER, the peptides can be sampled by newly synthesized MHC I molecules (figure 1) [1].

Loading of MHC I molecules — Newly synthesized polymorphic major histocompatibility complex (MHC) I heavy chains are assembled in association with an invariant polypeptide termed "beta-2-microglobulin." Peptide binding plays an active role in the initial assembly of the molecule, as MHC I molecules with no bound peptide are inherently unstable and will not assemble well until a peptide is bound. An important adaptor protein, tapasin, holds newly synthesized MHC I molecules adjacent to the TAP complex, where the local concentration of imported peptides is high, and retains them until they stably bind peptide. Only a relatively small subset of the peptides imported by the TAP complex will bind MHC I molecules, although ER-resident peptidases trim the peptides further to generate forms with improved affinity for MHC I [2].

Peptides that bind MHC I are limited in size (typically 8 to 10 amino acid residues in length), due to distinct structural features of the MHC I peptide-binding cleft. This cleft is closed at both ends [3]. Peptides are anchored into the MHC I molecule by their amino- and carboxy-termini, as well as by interior anchor residues. These anchor residues vary somewhat in position among different MHC I molecules but often include two hydrophobic side chains.

Regulation — MHC I-restricted antigen processing is ongoing in most nucleated cells. However, activation of the cell by exposure to microbes or inflammatory cytokines, particularly interferon (IFN) gamma, enhances the process through a variety of mechanisms. Three proteasome catalytic subunits (low-molecular-weight protein [LMP] 2, LMP7, and multicatalytic endopeptidase complex subunit 1 [MECL-1]) are expressed in response to IFN-gamma and replace constitutive subunits of the normal cellular proteasome [4]. Addition of these inducible subunits changes the activity of the proteasome to increase the proportion of peptide products suitable for binding to MHC I molecules, with significant effects on the repertoire of antigens presented [5]. In addition to these effects on proteasome activity, IFN-gamma-activated cells express higher levels of the TAP gene products, MHC I, and costimulatory molecules.

Activated professional APCs also express especially high levels of MHC I molecules. Together, these features confer upon professional APCs the unique ability to prime immune responses by cytotoxic T lymphocytes (CTLs) in the setting of an infection.

Monitoring of the extracellular environment — APCs monitor the extracellular environment by constantly taking up material from their surroundings and processing it principally through the MHC II-dependent antigen-processing pathway (figure 2).

Proper assembly and presentation of antigenic peptide:MHC II complexes is crucial for priming CD4+ (helper) T cell responses. These immune responses are directed toward extracellular bacteria, allergens, and particulate antigens shed by larger pathogens such as parasitic worms.

Antigen uptake — Tissue-resident macrophages and dendritic cells (DCs) are the primary cells that collect and process antigen from extracellular sources. Material is brought into the cell through phagocytosis, macropinocytosis, and receptor-mediated endocytosis.

●Phagocytosis of large molecules is principally carried out by macrophages. DCs also internalize large particulate antigens.

●Macropinocytosis, or the uptake of soluble antigens suspended in the extracellular fluid, is performed by immature DCs, such as epidermal Langerhans cells (LCs).

●Receptor-mediated endocytosis is performed by macrophages and DCs through a variety of cell surface molecules. These include antibody Fc receptors and complement receptors that bind bacteria and other large particles that have been coated (opsonized) with antibody and complement components. B lymphocytes accomplish receptor-mediated endocytosis through the action of surface immunoglobulin. (See "Regulators and receptors of the complement system".)

Receptor-mediated endocytosis is particularly important in secondary immune responses. High serum levels of specific opsonizing and complement-fixing antibodies are present in this setting. (See "The adaptive humoral immune response".)

Antigen processing — Proteins and particles internalized by any of the mechanisms previously mentioned are delivered to endosomes and lysosomes. Within the endocytic compartment, the proteins are degraded to peptides and loaded onto the MHC II proteins (figure 2).

The environment of the endosomal/lysosomal compartment provides conditions that facilitate highly efficient breakdown of protein antigens. The progressive acidification of vesicles along the endosomal pathway (reaching a pH of 4.5 to 5) is crucial for this process. The drug chloroquine, which inhibits lysosomal acidification, is a potent inhibitor of MHC II-restricted antigen presentation in vitro.

The cysteine and aspartyl proteases of the cathepsin family have specific roles in the MHC II-restricted pathway of antigen processing [6,7]. These enzymes are activated at low pH and are required for processing of many protein antigens. Cathepsins also play a central role in processing of nascent MHC II proteins to form peptide-receptive MHC II molecules.

Loading of MHC II molecules — Major histocompatibility complex (MHC) II alpha-beta heterodimers are assembled in the ER in complex with the invariant chain polypeptide (Ii) (figure 2). The Ii self-associates as a trimer, resulting in a (MHC II)3:Ii3 complex. The invariant chain serves two functions in this complex. It occludes the peptide-binding cleft, thereby preventing ER-resident peptides from binding, and it directs the MHC II:Ii complex to the endocytic pathway upon exit from the ER via a targeting signal in its cytoplasmic tail [8].

Upon reaching the endocytic compartment, the peptide-binding cleft must be made available to peptides of extracellular origin. To this end, the invariant chain is degraded by some of the same machinery that degrades extracellular protein antigens. This degradation proceeds in a stepwise fashion with identifiable intermediates, and specific cathepsin family members are required for the final processing steps. Tight regulation of the enzymes performing the key steps in this degradative pathway may represent an important point of control over MHC II-restricted antigen presentation in APCs [6]. The last portion of the invariant chain remaining associated with the MHC II molecule is a short peptide termed "CLIP" (for class II-associated invariant-chain peptide), which occupies the peptide-binding cleft (figure 2) [9].

The subsequent exchange of CLIP for peptides generated in the endosomal compartment is facilitated both by the acidic pH and by an MHC II-like molecule, the DM molecule. This molecule is a product of the human leukocyte antigen-DM (HLA-DM) locus and does not itself bind peptides. Instead, it catalyzes the displacement of CLIP and other low-affinity peptides from the peptide-binding cleft of MHC II molecules to favor the most stable complexes [10]. Stability of the peptide:MHC II complex at the cell surface is a critical determinant in the ability of a particular peptide to elicit an immune response. In this respect, it is important that DM not only facilitates the displacement of the CLIP peptide, but also continually displaces weakly binding peptides, resulting in a dynamic equilibrium where the peptide:MHC II complexes eventually transported to the cell surface are enriched for those with the longest half-lives [11]. While peptide dissociation is favored by low pH and the activity of DM in the endosomal compartment, peptide:MHC II complexes have extraordinarily long half-lives at neutral pH and in the absence of DM, which are the conditions found at the cell surface.

The MHC II molecules contain structural features that facilitate the formation of long-lived peptide:MHC complexes [12]. Peptides are anchored deeply in the peptide-binding groove, and an extensive hydrogen-bonding network between the peptide backbone and the amino acid residues lining the groove contributes considerably to their stability. In addition, MHC II molecules contain four to five pockets that accommodate prominent amino acid side chains from the peptide. The ends of the MHC II peptide-binding groove are open, allowing peptides of varying lengths to bind. This is a major point of contrast with MHC I molecules, in which the ends are enclosed and MHC I-bound peptides are restricted in length (see 'Loading of MHC I molecules' above). A brief review of the biosynthesis and processing of MHC molecules can also be found separately. (See "Transplantation immunobiology".)

While these features allow a large number of peptide sequences to bind MHC II molecules, the selectivity enforced by the size, shape, and biochemical nature of the peptide-binding grooves of different MHC II molecules provides a potential structural explanation for genetic associations of autoimmune disease with the expression of particular MHC II alleles. Most autoimmune diseases show strongest genetic linkage to alleles of MHC II genes, suggesting that antigen presentation to CD4+ T cells may play an important role in the development of autoimmune disease. The association of disease with one MHC II allele but not another may be a reflection of their effects on T cell repertoire selection during development and/or their differing abilities to bind and present specific peptide epitopes from important antigens. (See "Overview of autoimmunity".)

Regulation — The expression of MHC II molecules is largely restricted to macrophages, DCs, and B cells, which represents an important way in which the presentation of antigen is regulated.

A striking example of regulatory control of the MHC II-restricted antigen-processing pathway is seen during DC maturation. Although immature DCs in the tissues are exceptionally adept at antigen uptake, they process and present those antigens rather poorly. This is at least partly due to regulation at the level of processing of newly synthesized MHC II:Ii complexes. Immature DCs appear to retain an intracellular store of incompletely processed MHC II:Ii complexes, which are poised to enter the last stage of processing where they become receptive to peptides from exogenously derived proteins [13]. They consequently express very low levels of peptide:MHC II at the cell surface. In addition, immature DCs express very low surface levels of costimulatory molecules and display a chemokine-receptor profile that does not direct homing to lymph nodes [14]. (See 'T cell priming by APCs' below and "Transplantation immunobiology".)

DC maturation is induced by exposure to inflammatory stimuli, such as lipopolysaccharides, double-stranded ribonucleic acid (RNA), and other microbial products, mostly detected through members of the Toll-like receptor (TLR) family or cytokines produced early in the immune response to infection [15]. These stimuli induce increased MHC II and HLA-DM expression and upregulate costimulatory molecules. The fate of antigens derived from the extracellular space can be regulated by TLR activation at the level of individual endosomes [16]. Such a mechanism may serve to link each phagocytosed particle directly to information about its microbial (or nonmicrobial) source, thereby providing a fine distinction between antigens to be processed by immunogenic versus nonimmunogenic pathways within a single APC. (See "Toll-like receptors: Roles in disease and therapy".)

The maturing DC stops taking up new antigen and then exhibits a burst of antigen-processing activity and MHC II peptide loading and consequently expresses a wave of new peptide:MHC II at the cell surface. Simultaneously, there is a concomitant increase in expression of costimulatory and adhesion molecules, transforming the maturing DC into a potent T cell activator. Maturing DCs acquire a new chemokine-receptor profile that facilitates homing to lymph nodes and subsequently migrate out of the tissues and into the lymphatics where they will lodge in the draining lymph node to be sampled by circulating T lymphocytes [17]. In this manner, the mature DC delivers a "snapshot" of the antigenic environment from the point of exposure to the point of contact with large numbers of T cells in a strongly activating context.

While all DCs are regulated by this maturation pathway, there is also significant functional specialization among DC subsets [18]. Human DCs are broadly categorized as "conventional" (cDCs), "plasmacytoid" (pDCs), monocyte derived (MoDCs), and Langerhans cells (LCs). cDCs circulate in blood and tissues, and a subset of these (CD141+ cDCs) appears to be specialized for "cross-presentation" of extracellular antigens to CD8+ T cells. pDCs are found in blood and lymphoid organs, but rarely in nonlymphoid tissues at steady state, and produce large amounts of type I IFN in response to viral and fungal infections. MoDCs infiltrate inflamed tissues and perpetuate inflammation by inducing IFN-gamma and interleukin 17 production by CD4+ T cells, making them key cells of interest in autoimmune pathologies. LCs reside in the skin, are self-renewing, and are potent stimulators of both CD4+ and CD8+ T cell responses.

T CELL PRIMING BY APCs — Once an activated APC displaying high levels of major histocompatibility complex (MHC) I, MHC II, costimulatory molecules, and adhesion molecules migrates out of tissues and lodges in the peripheral lymphoid organs, it is sampled by circulating T cells. Naïve T cells recirculate through peripheral lymphoid tissues in a highly organized fashion through a series of cell-cell contacts. (See "Transplantation immunobiology".)

The productive interaction of a CD4+ T cell with an APC bearing the appropriate peptide:MHC II complex or a CD8+ T cell with one bearing the appropriate peptide:MHC I complex is the result of multiple stages of adhesion contacts and extensive cell surface reorganization by both cells.

Initial contact is mediated by large adhesion molecules that extend a considerable distance from the cell surface, such as the T cell integrin lymphocyte function-associated antigen 1 (LFA-1) and its ligand intercellular adhesion molecule 1 (ICAM-1) on APCs. These interactions are initially transient, but conformational changes in integrins signaled by T cell receptor (TCR) engagement strengthen the interaction to induce a firm adhesion between the cell membranes. Adaptor proteins anchoring cell surface molecules to the cytoskeleton then transmit actin reorganizations to the cell surface, creating a specialized focal contact point between cells where signaling and adhesion molecules become concentrated. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation".)

Large cell surface molecules are actively excluded from the focal point, allowing the smaller peptide:MHC and TCR proteins to interact extensively in a region of close membrane apposition. This highly organized contact point has been termed the "immunologic synapse," and its formation and duration facilitate a polarized, bidirectional exchange of membrane and soluble signals between the APC and the T cell [19]. The combination of TCR engagement by the appropriate peptide:MHC complex and T cell surface CD28 with CD80/CD86 molecules on the APC results in T cell entry into the cell cycle and development into effector CD4+ or CD8+ T cells.

CROSS-PRESENTATION PATHWAYS — Protein antigens entering an APC via the endocytic compartment are generally processed through the major histocompatibility complex (MHC) II-restricted pathway and presented to CD4+ T cells. Conversely, MHC I-bound peptides presented to CD8+ T cells are derived primarily from proteins synthesized within the cell's own cytosol. This segregation of pathways for exogenous versus endogenous antigens plays an important role in regulating immune responses. For example, it prevents the cytotoxic T lymphocyte (CTL) killing of healthy cells that have been exposed to viral or bacterial antigens but are not actually infected.

However, exogenous antigens are sometimes found in association with MHC I molecules, a phenomenon that has been termed "cross-presentation." The priming of T cells in this manner and the generation of CTL responses to exogenously derived antigens are called "cross-priming." Examples include CTL responses to allogeneic transplanted cells, tumor-associated antigens, viruses that do not infect APCs, and bacteria or parasites that do not enter the cytosol [20]. Cross-presentation is most efficiently performed by CD141+ conventional dendritic cells (cDCs) and Langerhans cells (LCs). These cells employ pathways of regulated intersection between the endocytic compartment and the MHC I-loading machinery that are not present in most cell types.

Two major types of intracellular processing pathways are implicated in cross-presentation [21]. The first is proteasome and transporter-associated with antigen processing (TAP) dependent, requiring endocytosed antigens to escape from the endosomal compartment to access the cytosolic protein-processing machinery [22]. The second is proteasome and TAP independent and relies on lysosomal proteases (cathepsins) to generate peptides [23]. Both pathways may involve the generation of a unique intracellular compartment containing elements of the normally endoplasmic reticulum (ER) confined MHC I loading machinery, endocytosed material, and newly synthesized or recycling MHC I molecules that are receptive to binding new peptides [24]. These specialized antigen delivery pathways and rerouting of normal MHC I trafficking for cross-presentation are activated by Toll-like receptor (TLR) signaling [25,26].

A detailed characterization of cross-presentation pathways is likely to aid in the development of a new generation of vaccines designed to elicit lasting cellular immunity to targets that require CTL activity, such as human immunodeficiency virus (HIV) and other pathogens, as well as tumor antigens.

PRESENTATION OF NONPEPTIDE ANTIGENS — While the canonical view of antigen presentation to conventional T cell subsets is highly focused on protein-derived (peptide) antigens, nonpeptide antigens such as lipids and small-molecule metabolites can also elicit T cell responses [27]. These pathways are governed by a set of nonclassical, nonpolymorphic major histocompatibility complex (MHC) I-like molecules known as CD1 and MHC I-related molecule 1 (MR1).

CD1 presentation of lipid antigens — Lipid and glycolipid antigens are presented by CD1 molecules [28]. The CD1 family of molecules is not encoded in the MHC gene cluster, although these proteins resemble an MHC I molecule in their general fold, and, like MHC I heavy chains, they assemble with beta-2-microglobulin. The most dramatic departure from MHC I structure in the CD1 molecules is in the antigen-binding cleft, which is deep and hydrophobic [29]. This structure is consistent with observations that CD1 molecules bind antigens composed of highly hydrophobic branched or dual acyl chains with hydrophilic head groups. The structure also provides some insight into how the CD1 molecule may bind the acyl tails of lipids in two prominent hydrophobic pockets, leaving the polar head group positioned for recognition by CD1-restricted T cell receptors (TCRs).

CD1 molecules traffic in a similar fashion to MHC II molecules due to an endosomal targeting motif in the cytoplasmic tail, indicating that they acquire antigen largely from the endocytic compartment [30].

CD1 molecules present lipid- and glycolipid-based antigens from both endogenous sources (including some typical cell membrane phospholipids) and microbial sources (such as those from mycobacterial cell wall components). CD1 proteins are divided into two groups: Group 1 CD1 proteins (CD1a, b, and c) are expressed predominantly on professional APCs, while group 2 (CD1d) is expressed more widely. Broadly speaking, group 1 CD1 molecules activate polyclonal populations of conventional alpha-beta T cells, while group 2 stimulates a population of innate-like natural killer T cells, expressing a highly restricted set of alpha-beta or gamma-delta TCR pairings.

While the clearest role for the CD1 pathway is in antimicrobial responses, it is also implicated in antitumor immunity and regulation of autoimmune responses. Both the full range of physiologic lipid antigens and the significance of CD1-restricted autoreactive T cell functions remain to be comprehensively elucidated. As lipids are synthesized through complex biochemical pathways with little potential for spontaneous variation, this lipid-based antigen presentation mechanism may represent an important evolutionary feature of the immune system for detecting antigens that are not easily altered by pathogens.

MR1 presentation of microbial metabolites — MHC I-related molecule 1 (MR1) is ubiquitously expressed at low surface levels by all cell types and activates another innate-like T cell subset known as mucosal-associated invariant T (MAIT) cells [31]. These cells express a highly restricted alpha-beta TCR and are abundant in the gut lamina propria and other mucosal surfaces. MR1 captures and presents short-lived vitamin B precursors derived from microbial synthesis of riboflavin by forming covalent adducts through a lysine residue located deep in the antigen-binding pocket. This complex stimulates MAIT cells to produce large quantities of inflammatory cytokines (interferon [IFN] gamma, tumor necrosis factor alpha, and interleukin 17) and the cytolytic factor granzyme-B. Activated MAIT cells kill MR1-expressing epithelial cells infected with some types of bacteria and fungi [32] and may exacerbate inflammatory bowel diseases [33].

COOPERATION BETWEEN T AND B CELLS — Antigen presentation by B cells plays a critical role in the development of a strong humoral immune response. Protein antigens taken up by B cell receptor-mediated endocytosis are processed through the major histocompatibility complex (MHC) II-restricted pathway, and peptides derived from them are presented to CD4+ helper T cells. In a phenomenon termed "linked recognition," the B cell must then encounter a CD4+ helper T cell that has been primed to the same antigen (but usually not the same epitope). Due to their expression of high levels of MHC II and costimulatory molecules of the B7 family (CD80 and CD86), B cells can also be the priming APC for helper T cells. B cells conjugated to activated helper T cells then establish germinal centers in the spleen and lymph nodes, where focused cell surface signals and polarized cytokine secretion by the activated helper T cell induce B cell expansion, affinity maturation, and immunoglobulin isotype switching. (See "The adaptive humoral immune response".)

CLINICAL APPLICATIONS — Knowledge of the functions and regulation of APCs is critical to understanding normal immune responses as well as the pathogenesis underlying infections, autoimmunity, allergic responses, tissue/organ transplant rejection, and the therapeutic immune response to tumors [34].

In addition, the functions of APCs can be manipulated to specific therapeutic ends. As examples, vaccination takes advantage of the natural role of APCs, while biologic agents such as abatacept and rituximab interfere with certain functions of APCs.

Diseases of APCs — Bare lymphocyte syndromes I and II are immunodeficiency disorders that arise from abnormalities in the expression of major histocompatibility complex (MHC). These diseases are discussed in detail separately. (See "CD3/T cell receptor complex disorders causing immunodeficiency".)

APC-based therapies — Therapies that manipulate APC function include vaccines and certain biologic therapies.

Vaccination — The practice of inoculating individuals with attenuated or killed bacteria and viruses began over two centuries ago based on the empirical observation that this could induce protective immunity to some infectious agents. While this idea developed in the absence of any real knowledge of the underlying mechanisms of immunity, the modern understanding of molecular events involved in antigen presentation and the development of cellular and humoral immune responses has fostered dramatically different ideas about vaccine development. In addition to whole organism approaches, which have worked well for some pathogens but have not yielded solutions for some of the world's most important human infections (human immunodeficiency virus [HIV], malaria, tuberculosis), recombinant purified antigens and novel delivery systems are being increasingly applied in new vaccine design efforts.

The first recombinant subunit vaccine, the hepatitis B surface antigen vaccine, was based on a single purified viral protein produced in yeast [35] and has had great success in widespread usage. This vaccine works by inducing a strong CD4+ T cell and antibody response to the viral capsid when processed by the MHC II-restricted antigen-processing pathway (see "Hepatitis B virus immunization in adults"). In addition, the human papilloma virus (HPV) L1 subunit vaccines [36] introduced in 2006 have proven highly successful [37]. Ongoing research into the mechanisms of MHC I-restricted antigen presentation and cross-presentation pathways opens the additional possibility of inducing targeted CD8+ T cell responses to specific antigens using vaccination strategies that deliver antigen directly into specialized antigen-processing pathways.

New vaccines will also benefit from a new generation of synthetic adjuvants based on a molecular understanding of how the toll family of pattern recognition receptors initiates innate immune responses and activates APCs to set the stage for long-lasting adaptive immunity. (See "Toll-like receptors: Roles in disease and therapy".)

Novel strategies are being developed to optimize antigen delivery based on specific knowledge of how different types of antigens interface with APCs. An exciting line of research in this area uses antibodies directed toward dendritic cell (DC) endocytic receptors to deliver antigens to specific cell subsets [38].

APC-based cancer immunotherapy — The potent T cell-priming properties of professional APCs have been exploited to develop experimental cell-based therapies for various cancers [39]. Human DCs can be cultured from peripheral blood samples, loaded with potential tumor antigens, activated in vitro, and then returned to a patient in an autologous transplant. Both the type of activating stimulus used and the route of antigen entry into the processing pathways are critical parameters. A vaccine against prostate cancer has been shown to prolong overall survival and is approved for patients with advanced disease. (See "Principles of cancer immunotherapy", section on 'Vaccines'.)

Agents that block APC function — Abatacept is a biologic agent that blocks costimulation by APCs. It is a soluble fusion protein comprising cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and the Fc portion of immunoglobulin G1 (CTLA4-Ig). Abatacept prevents CD28 from binding to its counter-receptor, CD80/CD86, due to its higher affinity for CD80/CD86. It is used in severe rheumatoid arthritis. (See "Overview of biologic agents in the rheumatic diseases", section on 'Costimulation blockade'.)

The detailed understanding of positive and negative costimulatory pathways used by APCs to regulate T cell activity has also led directly to the development of the immune checkpoint inhibitor class of highly promising cancer therapeutics. (See "Principles of cancer immunotherapy".)

Rituximab is an anti-CD20 monoclonal antibody that interferes with the ability of B cells to function as APCs. CD20 is a B lymphocyte-specific molecule, which is expressed on B cells beginning at the pre-B cell stage and is normally lost as B cells differentiate into plasma cells. Rituximab causes depletion of B cells expressing CD20, thus interfering with their antigen-presenting functions while sparing the antibody-producing function of plasma cells. It is approved for use in severe rheumatoid arthritis. (See "Normal B and T lymphocyte development" and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

SUMMARY

●Antigen-presenting cells – To stimulate an adaptive immune response, an antigen must be processed and presented in recognizable form to T cells with the appropriate concomitant signals. The cells that perform these functions are antigen-presenting cells (APCs). The primary APCs are macrophages, dendritic cells (DCs), and B lymphocytes. (See 'Professional APCs' above.)

●APC functions – APCs have four primary functions (see 'Major functions' above):

•Monitoring the intracellular and extracellular environments – Intracellular protein antigens are processed and presented in association with major histocompatibility complex (MHC) I molecules (figure 1). APCs presenting antigens processed in this manner stimulate CD8+ cytotoxic T cell responses, resulting in killing of cells that have been infected with viruses or other intracellular pathogens. (See 'Monitoring the intracellular environment' above.)

•Processing antigens through specific pathways:

-Intracellular protein antigens are processed and presented in association with major histocompatibility complex (MHC) I molecules (figure 1). APCs presenting antigens processed in this manner stimulate CD8+ cytotoxic T cell responses, resulting in killing of cells that have been infected with viruses or other intracellular pathogens. (See 'Monitoring the intracellular environment' above.)

-Extracellular protein antigens are processed and presented in association with MHC II molecules (figure 2). APCs presenting antigens processed via this pathway activate CD4+ helper T cells, leading to specific antibody production and a humoral immune response. This type of response is important in defense against extracellular bacteria, parasites, and in allergic disease. (See 'Monitoring of the extracellular environment' above.)

-Nonpeptide antigens such as lipids and metabolites are presented by the MHC-like molecules CD1 and MHC I-related molecule 1 (MR1). (See 'CD1 presentation of lipid antigens' above.)

•Transporting antigens from tissues to the peripheral lymphoid organs and activating T cells – Activated APCs migrate out of tissues to peripheral lymphoid organs, where they are "sampled" by circulating T cells. If the presented antigen is recognized by a T cell and appropriate costimulatory signals are present, that T cell divides and gives rise to a population of T cells that are specific to the antigen in question. These cells then disperse and effect an immune response directed against that antigen. (See 'T cell priming by APCs' above.)

●Clinical applications – Vaccination takes advantage of the natural role of APCs, while biologic agents such as abatacept and rituximab interfere with certain functions of APCs. (See 'Clinical applications' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.