Neutrophils

Following release from the bone marrow, neutrophils are normally present in blood for a short time (half-life about 5 to 10 hours) before they egress into the tissues.^{75,116,383,433} Neutrophils appear to survive no more than a few days in tissues.⁴³³ Neutrophils that remain in blood spontaneously undergo apoptosis and are removed by macrophages in the spleen, liver, and bone marrow via a phagocytic process (termed efferocytosis) that does not generate an inflammatory reaction.^162,328,422

Neutrophils occur in circulating and marginating pools in blood, with 50% or less of the total blood neutrophil pool being present in the circulating pool (Fig. 5-5).^226,433 The circulating neutrophil pool (CNP) is assessed by routine blood sample collection. The marginating neutrophil pool (MNP) consists of neutrophils that are transiently retained in capillaries and veins. The lung has long been considered the predominant organ contributing to the MNP^121,309; however, recent studies suggest that the liver, spleen, and bone marrow may contribute substantially to the MNP.⁴⁴⁵ The retention of neutrophils in the vasculature does not appear to involve neutrophil adhesion to endothelial cells.²⁶⁰ The size of the MNP in an organ is related to its blood flow and the neutrophil intravascular transit time through the organ.⁴⁴⁵ Neutrophil margination is increased in lungs when blood flow is reduced and decreased when blood flow is increased.⁴⁵⁵ The absolute neutrophil count measured in blood samples can be affected by cell movements between the MNP and CNP. A net movement of neutrophils from the MNP to the CNP increases the circulating blood neutrophil count. A net movement in the opposite direction results in a decreased circulating blood neutrophil count.⁴³⁵

FIGURE 5-5 Neutrophil distribution in blood. Neutrophils occur in the circulating neutrophil pool (CNP) and marginating neutrophil pool (MNP), with 50% or less of the total blood neutrophil pool being present in the CNP.

Eosinophils and Basophils

The half-life reported for human eosinophils ranges from 8 to 18 hours.³⁶⁸ Little information is available concerning blood basophil kinetics, but a half-life of 2 to 3 days has been reported for humans.⁴⁴⁰ Basophils appear to survive no more than a few days in tissues.¹⁶⁴ In contrast, eosinophils may remain in tissues for weeks to months unless they migrate into airways or the gastrointestinal tract.⁴⁷⁸

Monocytes

The half-life for monocytes in blood is reported to vary from 0.5 to 3 days in rabbits, mice, and humans.^185,506 Monocytes also have a marginating pool within pulmonary capillaries.¹²¹ Monocytes develop into macrophages and dendritic cells in the tissues, where they survive for variable time periods.⁵⁰⁶ Macrophages may survive up to 3 months in tissues.¹⁶⁵ Dendritic cells in lymphoid organs are reported to survive 10 to 14 days.²⁸⁴ In contrast, dendritic cells in skin (Langerhans cells) are reported to survive more than a year.³²²

Lymphocytes

Most lymphocytes reside within lymphoid organs (lymph nodes, thymus, spleen, and bone marrow). Only about 2% to 5% of lymphocytes circulate in blood.^50,458 Like neutrophils and monocytes, lymphocytes have a MNP within pulmonary capillaries.^121,455 Depending on the species and individual variability, about 50% to 75% of blood lymphocytes are T lymphocytes and about 10% to 40% are B lymphocytes. NK cells account for 5% to 10% of blood lymphocytes.⁴⁵⁸ Some NK cells appear as granular lymphocytes, but not all. A subset of CD8⁺ T lymphocytes also appear as granular lymphocytes.³³

A majority of blood lymphocytes are naive T and B lymphocytes, and most of the remaining blood lymphocytes are antigen-primed memory T and B lymphocytes.¹⁴⁰ The fraction of memory lymphocytes increases and the fraction of naive lymphocytes decreases in the blood of humans as they age.²⁹³ Most lymphocytes in blood have come from peripheral lymphoid organs (primarily lymph nodes). Lymphocytes circulate for a short time in blood (half-life about 30 minutes), exit, migrate through lymphoid tissues (and to some degree extralymphoid tissues), and return to blood via lymphatics.⁵⁰ B and T lymphocytes migrate through lymph nodes with average velocities of around 6 and 12 µm/min, respectively. It is estimated that it takes about 1 day for a recirculating lymphocyte to migrate through a lymph node.^40,507 Recirculation allows lymphocytes, with their complete repertoire of unique antigen receptors, to be available for immune reactions throughout the body.

Naive lymphocytes have a propensity to recirculate through lymph nodes. They migrate into lymph nodes through high endothelial venules (HEVs) because these venules have adhesion molecules and chemokines on their surfaces that recognize complementary adhesion and chemokine receptors expressed on naive lymphocyte surfaces.³⁹⁹ Recirculating lymphocytes generally exit the lymph nodes via the efferent lymphatics; however, they appear to emigrate from lymph nodes via paracortical postcapillary venules in pigs.⁵¹ Efferent lymphatics join together to form large lymphatic vessels, the largest of which is the thoracic duct, and drain into the blood at the level of the heart (Fig. 5-6).

FIGURE 5-6 Circulation routes for lymphocytes. Solid lines represent blood vessels and dashed lines represent lymphatic vessels. Naive lymphocytes circulate primarily through lymph nodes and memory lymphocytes circulate through tissues.

Dendritic cells are exposed to antigens in tissues and migrate to draining lymph nodes. When naive T and B lymphocytes are exposed to their cognate antigens presented by dendritic cells in lymph nodes, they proliferate and form effector lymphocytes and long-lived memory lymphocytes. Dendritic cells present not only antigens but also environmental signals (including vitamin A and D₃ metabolites) that program migration pathways.⁴²⁸ Memory lymphocytes develop an array of adhesion molecules and chemokine receptors that target their subsequent migration to specific tissues including skin, intestinal mucosa, and lungs.^50,399 Tissue lymphocytes are picked up by afferent lymphatics and are carried to lymph nodes, where they exit by efferent lymphatics, traverse large lymphatic vessels, and reenter the blood (see Fig. 5-6). Most plasma cells and proliferating lymphocytes, such as those present in germinal centers, do not express the adhesion molecules necessary for migration.⁴⁵⁸

Lymphocytes generally survive much longer than granulocytes. Naive T lymphocytes are reported to have a half-life of about 40 days in mice. CD8⁺ memory T lymphocytes and some CD4⁺ memory T lymphocytes are long-lived in mice (many months), but other CD4⁺ memory T lymphocytes survive only about 2 months. Memory T lymphocytes are reported to survive for many years in humans.³⁰⁹ Long-term survival may require cell proliferation; therefore it may be a matter of semantics whether long-term survival refers to an individual lymphocyte or a population of lymphocytes.

The t_1/2 disappearance rate for B lymphocytes from the recirculating pool is reported to be 2 to 3 weeks in humans. Long-term-memory B lymphocytes appear to be maintained as proliferating clones of cells rather than as individual cells that survive for a long time.²⁹³ Plasma cells survive for variable periods of time. Those that develop in sites of inflammation disappear when the inflammation is resolved. However, some plasma cells may survive for years in humans, especially within stromal niches in bone marrow.³³⁹

An NK cell’s half-life in the circulation is about 7 to 10 days in mice and 12 days in humans under normal conditions. NK cells leave the circulation by entering tissues during steady-state conditions or through cell death. NK cell survival is promoted by the cytokine, interleukin-15 (IL-15).⁵¹³ NK cells are located in many organs including spleen, lung, bone marrow, lymph nodes, liver, intestine, skin, and thymus (low numbers). Some NK cells recirculate through blood and lymph.^117,187 The spleen and bone marrow appear to provide NK cell reserves that can rapidly enter the blood and subsequently migrate into tissues in response to inflammation. NK cell migration from blood to inflammatory sites occurs by mechanisms similar to those described for granulocytes. These include initial adhesion to endothelial cells via selectins, followed by tighter adhesion to endothelial cells via integrins and chemoattractant-directed migration. Chemoattractants include certain chemokines as well as bacterial products, leukotrienes, and C5a. Marked infiltrates of NK cells are also present in the uterus during pregnancy.¹⁸⁷

Neutrophil Functions

Neutrophils are essential in the defense against invading microorganisms, primarily bacteria. To be effective, they must recognize inflammatory signals, leave the blood, migrate through tissue to a site where bacteria are present, and then neutralize the bacteria. Neutrophils display glycoprotein adhesion molecules on their surfaces that are needed for various adhesion-dependent functions, including adhesion to endothelium and subendothelial structures, spreading, haptotaxis, and phagocytosis.¹⁰⁶ Unless they are activated, neutrophils and endothelial cells exhibit little tendency to adhere to each other. Following the stimulation of endothelial cells by mediators—such as thrombin, histamine, and oxygen radicals—P-selectin is rapidly mobilized from storage granules and expressed on the surfaces of endothelial cells. Inflammatory mediators, including interleukin-1 (IL-1) and tumor necrosis factor (TNF), promote the expression of E-selectin adhesion molecules on the surface of activated endothelial cells within 1 to 2 hours.⁵⁸ These oligosaccharide-binding selectin molecules, acting in concert with the L-selectin adhesion molecule expressed on the surface neutrophils, bind to their counterligands, most notably P-selectin glycoprotein ligand-1 (PSGL-1), which results in the initial adhesion of unstimulated neutrophils to activated endothelial cells (Fig. 5-7).⁵¹¹ As a result of selectin binding between neutrophils and activated endothelial cells, the velocity of neutrophils in the circulation is markedly decreased and they are seen to roll along the endothelium.⁵¹⁰

FIGURE 5-7 Endothelial cell activation, neutrophil rolling along vessel walls, tight adhesion between neutrophils and endothelial cells, diapedesis, and haptotaxis.

Activated endothelial cells produce factors including interleukin-8 (IL-8) and platelet activating factor (PAF, a biologically active phospholipid) that result in neutrophil activation. Other mediators that can activate neutrophils include opsonized particles, immune complexes, N-formylated bacterial peptides, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and chemoattractants produced during inflammation.⁵⁸ Neutrophil activation results in increased expression and enhanced binding affinity of β₂ integrin adhesion molecules and shedding of L-selectin molecules. β₂ integrins (CD11a,b,c/CD18) are heterodimers that bind with variable affinity to intercellular adhesion molecules (ICAMs). β₂ integrin binding further slows rolling and ultimately results in the firm adhesion of neutrophils to endothelial cells. Adherent (activated) neutrophils then spread and exhibit pseudopod formation. Neutrophil activation also promotes degranulation, superoxide generation, and the production of arachidonate metabolites, to be discussed later.⁵⁸

In addition to increased β₂ integrin affinity, activated neutrophils have increased numbers of surface receptors and/or enhanced receptor affinity for chemoattractants.⁴³² These receptors are also found in granules, suggesting that they are mobilized to the cell surface during neutrophil activation. When they are exposed to chemoattractants, neutrophils penetrate the wall of postcapillary venules, primarily by moving between endothelial cells.⁵⁸ Less than 5 minutes is required for neutrophils to pass between endothelial cells, but 15 minutes or more may be required for them to pass through the vascular basement membrane.²⁷⁷ Once outside the vessel, the active directional migration of neutrophils in tissues occurs largely by haptotaxis, which means migration up a gradient of immobilized chemoattractants rather than soluble chemoattractants (chemotaxis). A wide variety of substances can function as a chemoattractant, including IL-8 and other chemokines, C5a (complement fragment), leukotriene B₄ (a product of arachidonic acid metabolism via the lipoxygenase pathway), PAF (1-0-alkyl-2-acetyl sn-glyceryl phosphorylcholine) and bacterial products (e.g., N-formyl-methionyl oligopeptides) recognized by Toll-like receptors.^58,106

During their movement toward increasing concentrations of chemoattractants, neutrophils become elongated, with a frontal pseudopod extending in the direction of movement and a distal uropod that consists of fine trailing appendages. Membrane sheets (lamellipodia) on the leading edge of the pseudopod are in continual motion, orienting in the direction of chemoattractants.⁴⁴¹ Neutrophils crawl (10-12 µm/min) toward the source of the chemoattractant by the binding of integrin surface molecules to their respective ligands within the extracellular matrix at the frontal pseudopod and detaching from these ligands at the distal uropod. Although present in only small amounts on the surfaces of circulating blood neutrophils, activated neutrophils express increased surface β₁ integrins, which appear to be the most important class of integrins for migration. Members of the β₁ integrin family have high affinity for proteins in the extracellular matrix, including collagen, laminin, fibronectin, and vitronectin.²⁸⁰ Movement depends on actomyosin-mediated contractions at the leading edge for pseudopod advancement and in the trailing end to break adhesive contacts.⁴⁴¹

For phagocytosis to occur, neutrophils must be able to first bind invading bacteria to their surfaces (Fig. 5-8). This adherence is greatly potentiated if bacteria have been opsonized (have antibodies and complement components bound to their surfaces) because neutrophils have immunoglobulin Fc and C3b receptors on their surfaces. Following binding, bacteria are engulfed by the neutrophils’ cytoplasmic processes, which extend around the organisms. The membranes of the neutrophils’ cytoplasmic processes fuse to form phagocytic vacuoles surrounding the engulfed bacteria.^58,106

FIGURE 5-8 Basic events involved in the phagocytosis, killing, and the discharge of killed bacteria and degraded bacterial products.

Bacterial killing involves a multitude of mechanisms that are set into motion by two cellular events, initiation of the respiratory burst and degranulation. The respiratory burst is initiated by the activation of an NADPH oxidase enzyme (Fig. 5-9). This enzyme is normally “inactive” in resting or unstimulated phagocytes. Enzyme activation depends on the assembly of multiple components, some of which are already membrane-bound and others that must be translocated from the cytoplasm to the membrane. Activated NADPH oxidase is located in the plasma membrane and becomes incorporated into the phagocytic vacuole. It catalyzes the one-step reduction of O₂ to form superoxide (O₂⁻).¹⁰⁶ The NADPH needed to generate superoxide is formed in the pentose phosphate pathway. The superoxide thus formed undergoes dismutation to form hydrogen peroxide, as shown below:

FIGURE 5-9 Generation of superoxide free radicals by the membrane-associated NADPH oxidase enzyme.

Hydrogen peroxide and superoxide can diffuse from the phagocytic vacuole into the cytoplasm of the cell. Activated neutrophils utilize the superoxide dismutase and glutathione peroxidase reactions to protect themselves from these oxidants. The latter reaction requires that additional NADPH be generated to maintain glutathione in the reduced form. Activation of the respiratory burst requires neither phagocytosis nor degranulation to occur. In addition to opsonized particles, chemoattractants, such as C5a, can activate the respiratory burst.¹⁰⁶

Superoxide, other free radicals (e.g., hydroxyl radical), and H₂O₂ may be involved directly in the killing of bacteria, but killing is potentiated by degranulation, which results in the fusion and release of the contents of lysosomal granules into the phagocytic vacuole (see Fig. 5-8). Myeloperoxidase is an iron-containing enzyme located in the primary granules of neutrophils. The myeloperoxidase reaction greatly enhances the bactericidal potency of H₂O₂. This reaction catalyzes the oxidation of chloride to hypochlorous acid, resulting in halogenation of bacterial cell walls (see below) and loss of integrity.¹⁰⁶

Other enzymes are also present in primary and secondary granules of neutrophils.⁴³² These include collagenase, acid and neutral hydrolases, and lysozyme, which hydrolyzes glycosidic linkages in the cell walls of certain bacteria. These enzymes are probably more important in digestion than in killing. Nonenzymatic agents are also involved in neutrophil defense. A number of cationic proteins and peptides in neutrophil granules have antimicrobial properties.⁴³² Of these molecules, defensins appear to be the most common. With the lowest molecular weight, defensins are small (4 kD) antimicrobial peptides within primary granules that act against bacteria and other microorganisms by altering their membrane permeability. They are inserted into the lipid bilayer, disrupting interaction between lipid molecules. In addition, lactoferrin occurs within secondary granules and chelates iron required for microbial growth.⁴³²

The growth factors G-CSF and GM-CSF are important, not only in the production of neutrophils but also in promoting neutrophil survival and function. G-CSF and GM-CSF are produced by macrophages, neutrophils, and other cell types at inflammatory sites.¹³⁷ They prime neutrophils in ways that enhance their functions and inhibit apoptosis of neutrophils at sites of inflammation.^106,360 Neutrophils become more adhesive and responsive to other stimuli, including chemoattractants, and their respiratory burst is enhanced after they bind these growth factors.^{106,137,304,499}

Following the killing and digestion of bacteria, the phagocytic vacuole fuses with the plasma membrane and discharges the killed bacteria, products of degraded bacteria, and contents of granules to the outside of the cell in a process called exocytosis (see Fig. 5-8). Discharge of granules can also occur following activation of neutrophils in the absence of phagocytosis. Considerable tissue injury occurs in areas where neutrophils are activated because of the oxidants they produce and the granule contents they release.

Neutrophils can trap and kill bacteria and fungi without phagocytosis by releasing neutrophil extracellular traps (NETs). These NETs consist of fibers (composed of DNA, histones, and proteins from granules) that can kill microbes.¹⁵⁸ Initial reports indicated that these NETs were generated by neutrophils undergoing cell death¹⁵⁸; however, more recent reports indicate that NET formation can occur without neutrophil death.^365,509 NET production is an active process, not the result of leakage during cellular disintegration. The NETs formed by living neutrophils contain mitochondrial DNA but no nuclear DNA.⁵⁰⁹ In addition to mammalian neutrophils,^192,477 neutrophils from fish and heterophils from birds produce NETs when they are appropriately stimulated.^85,365

Several pathogens have co-opted phagocytic and killing processes to survive within phagocytes. These include Listeria, Yersinia, and Mycobacterium species.¹⁰⁶

Eosinophil Functions

Most tissue eosinophils reside in the gastrointestinal mucosa.³³⁵ Eosinophils have less phagocytic ability than neutrophils and provide poor host defense against bacterial or viral agents.²⁰⁷ However, eosinophils are an important component of the type 2 cytokine-induced inflammatory response that is critical in the host defense against helminth infections and is responsible for the pathogenesis of type 1 hypersensitivity allergic reactions. CD4⁺, type 2 helper T (T_H2) lymphocytes secrete a group of cytokines that result in the recruitment and/or activation of effector cells including B lymphocytes producing IgE, mast cells, basophils, and eosinophils.³⁴⁶

Rather than simply responding to an otherwise innocuous environmental antigen by producing IgG or IgA antibodies, some animals respond to environmental antigens with an exaggerated T_H2 response that produces excessive amounts of IgE. IL-4 and IL-13 from T_H2 lymphocytes and the presence of activated mast cells, basophils, and eosinophils stimulate B lymphocytes to switch to IgE production.^381,431 This excess IgE binds to receptors (FcεRI) on mast cells in the tissues and primes the mast cells to bind the environmental antigen (allergen) that stimulated the IgE response. When the primed mast cell encounters the allergen and it cross-links two of the bound IgE molecules, the mast cell will degranulate and release a mixture of inflammatory mediators and potent chemoattractants for eosinophils into the surrounding tissues.⁴⁵⁸ These chemoattractants include histamine and small C-C chemokine proteins, including eotaxins (CCL11, CCL24, and CCL26) and CCL5, which appear to be particularly important in the selective recruitment of eosinophils. Other factors such as PAF and leukotriene B₄ also function as chemoattractants, but these factors are not specific for eosinophils. T_H2 lymphocytes and activated mast cells produce factors (IL-5, IL-3, and GM-CSF) that not only stimulate the production and release of eosinophils but also activate eosinophils and promote their survival.⁴⁵⁸

Helminths stimulate both humoral and cellular immunity, but they are resistant to killing by conventional immune mechanisms. B lymphocytes produce IgG antibodies that may bind to the parasites, but their extracellular cuticles cannot be penetrated by the complement membrane attack complex or T lymphocyte perforins. As previously discussed for allergens, specific IgE antibodies against parasite antigens are also produced, and these IgE molecules bind to mast cells. The binding of parasite antigens to these IgE antibodies results in mast cell activation and degranulation and release of inflammatory mediators and potent chemoattractants for eosinophils.⁴⁵⁸

Like molecules associated with neutrophil adhesive processes, selectins and β₂ integrins are involved in eosinophil adhesion to activated endothelial cells. In addition, endothelial cells activated by IL-4 and IL-13 express vascular cell adhesion molecule-1 (VCAM-1), which binds to very late antigen-4 (VLA-4) on the surfaces of eosinophils. This integrin is not expressed on neutrophils and presumably helps to provide specificity for eosinophil localization.⁴⁷⁸

Eosinophils migrate into the tissues in response to chemoattractants generated in response to helminths. Initially, migration is stimulated primarily by mast cell- and/or parasite-derived attractants, including chitin (N-acetyl-beta-D-glucosamine), a widespread polymer that provides structural rigidity to helminths, insects, crustaceans, and fungi.³⁹³ A second wave of migration is supported by IL-5 and other cytokines produced by T_H2 lymphocytes.⁴⁵⁸

Eosinophils bind to the opsonized parasites via their surface receptors to IgG and complement. The parasites are much too large for eosinophils to ingest, but when activated, eosinophils exhibit dramatic NADPH oxidase activity, which generates extracellular oxidants. They also exocytose their granules in the area of the invading parasite. Eosinophil peroxidase released from granules interacts with hydrogen peroxide generated from the respiratory burst and halide ions. This complex—along with other oxygen metabolites, major basic protein, eosinophil cationic protein, and eosinophil neurotoxin released from secondary granules—is primarily involved in the killing of helminths.^458,478

The eosinophil has been perceived as a terminal effector cell in the T_H2 inflammatory response. However, recent work indicates that eosinophils have the ability to modulate T lymphocyte responses. Eosinophils can present antigens to T lymphocytes and produce cytokines (primarily IL-4 and IL-13) that induce T_H2-cell development and recruit additional T_H2 cells to sites of inflammation.⁴³⁸

Basophil Functions

Basophils generally occur in low numbers in the circulation. They contain most of the histamine measured in blood. Histamine in granules is bound to proteoglycans (such as chondroitin sulfate and heparin), which are responsible for the metachromatic staining (purple color with blue dyes) of the granules. Basophils have biochemical characteristics similar to those of mast cells and share a common progenitor cell with mast cells in bone marrow, but they are clearly different cell types.¹⁶⁴ Basophils have segmented nuclei and mast cells have round nuclei. Mast cells usually have more cytoplasmic granules than basophils. In cats, both primary and secondary granules in basophils are morphologically different from mast cell granules.

Basophils have functions similar to those of mast cells, including being important in the protective immunity against helminths.³⁶¹ In contrast to mast cells, which develop and reside in tissues, basophils are recruited from blood into sites of inflammation after exposure to allergens, helminths, and ectoparasites.⁴⁷⁶ Among chemoattractants, chemokines that bind to C-C chemokine receptor type 3 (CCR3) are the most potent basophil chemoattractants. These chemokines include the eotaxins (CCL11, CCL24, and CCL26) and CCL5, CCL7, and CCL13.⁴⁷⁰ IL-33 has recently been identified as an interleukin that targets basophils. It enhances histamine release by IgE-dependent stimuli as well as the secretion of IL-4, IL-8, and IL-13 by blood basophils. IL-33 may also help regulate basophil binding to endothelium and migration into the tissues.⁴⁷⁰

Following the binding of an antigen to a specific, surface-bound IgE antibody, basophils are activated and release histamine and other mediators that contribute to the inflammation present in immediate hypersensitivity reactions. In addition to IgE-mediated antigenic activation, other substances including C5a, various bacterial peptides, and chemokines can also activate basophils.⁴⁷⁰ Recent studies reveal that basophils perform essential nonredundant functions in T_H2 cytokine-dependent immunity. In particular, basophils migrate to lymph nodes and function as antigen-presenting cells, which appears to be critical for the induction of T_H2-cell differentiation.^411,431 In concert with IL-3, stem cell factor (SCF) prolongs basophil survival by delaying apoptosis.²⁰⁸

Monocyte/Macrophage/Dendritic-Cell Functions

Lymphocyte and NK Cell Functions

Lymphocytes are divided into T lymphocytes, B lymphocytes, and NK cells. A thorough discussion of the functions of these cells is beyond the scope of this text; the reader is therefore referred to immunology textbooks such as the one by Tizard⁴⁵⁸ for more detailed information.

T lymphocytes are largely responsible for cellular immunity. They are involved in immune regulation, cytotoxicity, delayed-type hypersensitivity, and graft-versus-host reactions. T lymphocytes are also actively involved in the control of hematopoiesis. To produce these effects, different subpopulations produce a large number of cytokines with diverse biological activities. Most T lymphocytes express TCRs composed of α and β chains. These TCRs recognize peptide antigens bound to MHC-I or MHC-II molecules. Peptides bound to MHC-I molecules are synthesized intracellularly by most cell types in the body, while peptides bound to MHC-II molecules are formed from extracellular antigens that have been endocytosed and processed by professional antigen-presenting cells, with dendritic cells being most important. Surface proteins CD8 and CD4 are coreceptors that bind to MHC-I and MHC-II, respectively.⁴⁵⁸

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