Mucosal Immunity - Comprehensive Notes

Mucosal Immunity

Aim

The primary aim of mucosal immunity is to protect against the invasion of pathogens through mucosal surfaces, maintaining a balance between immune responses and tolerance to commensal microbes and harmless antigens.

Objectives

• Describe the organization of mucosa-associated lymphoid tissue (MALT) and its role in initiating immune responses.

• Explain the mechanisms of antigen passage across the gut wall, including M-cells and dendritic cells, and the subsequent stimulation of the immune response.

• Describe the cell types present in Peyer's patches and their functions in antigen processing and lymphocyte activation.

• Explain the transport of IgA antibodies into the gastrointestinal tract and their role in neutralizing pathogens.

• Describe the trafficking of lymphocytes to and from MALT, including the homing receptors and chemokines involved.

Mucosal Tissues

The mucosal tissues in the human body include:

• Lachrymal gland and conjunctiva: Detailed anatomy includes the lacrimal gland's acinar structure, responsible for tear production, and the conjunctiva's goblet cells, which secrete mucins for lubrication. Histologically, the lachrymal gland consists of serous acini and ducts, while the conjunctiva is stratified columnar epithelium with interspersed goblet cells. Their primary function is protecting the eyes from pathogens through continuous washing and immune surveillance. Common infections include conjunctivitis (pink eye) and dacryoadenitis (inflammation of the lacrimal gland), triggering local immune responses involving increased vascular permeability and leukocyte infiltration.

• Oral cavity, sinus, and salivary gland: The oral cavity's anatomy includes the tongue, teeth, and hard and soft palates. The sinuses are air-filled spaces lined with respiratory epithelium, and the salivary glands (parotid, submandibular, sublingual) produce saliva containing antimicrobial enzymes like lysozyme and salivary amylase. Histologically, the oral mucosa is stratified squamous epithelium, the sinuses are pseudostratified ciliated columnar epithelium, and the salivary glands contain acinar and ductal cells. These tissues provide a first line of defense against ingested and inhaled pathogens. Common infections include dental caries, sinusitis, and salivary gland infections (sialadenitis), which elicit immune responses such as increased IgA production and localized inflammation.

• Trachea, respiratory tract, and lungs: The trachea is a cartilaginous tube lined with respiratory epithelium, branching into bronchi and bronchioles within the lungs. The lungs consist of alveoli, where gas exchange occurs, and are highly vascularized. Histologically, the trachea and bronchi are pseudostratified ciliated columnar epithelium with goblet cells, while the alveoli are simple squamous epithelium. These tissues are critical for gas exchange and vulnerable to airborne infections, defended by the mucociliary escalator and alveolar macrophages. Common infections include bronchitis, pneumonia, and influenza, triggering immune responses such as increased mucus production, recruitment of immune cells, and antibody production.

• Gastrointestinal tract (esophagus, stomach, intestine): The esophagus is a muscular tube connecting the oral cavity to the stomach, which is a muscular organ with a highly acidic environment. The small intestine (duodenum, jejunum, ileum) is the primary site of nutrient absorption, and the large intestine absorbs water and electrolytes. Histologically, the esophagus is stratified squamous epithelium, the stomach is simple columnar epithelium with gastric pits, and the intestines are simple columnar epithelium with villi and microvilli. The gastrointestinal tract is responsible for nutrient absorption and a major site of pathogen entry, protected by gastric acid, mucus, and gut-associated lymphoid tissue (GALT). Common infections include gastroenteritis, peptic ulcers, and inflammatory bowel disease, leading to immune responses like increased IgA production, T-cell activation, and localized inflammation.

• Urogenital tract (kidney, bladder, uterus, vagina): The kidneys filter blood and produce urine, which is stored in the bladder. The uterus supports fetal development during pregnancy, and the vagina is the birth canal. Histologically, the kidneys contain nephrons with glomeruli and tubules, the bladder is transitional epithelium, the uterus is endometrium with glands, and the vagina is stratified squamous epithelium. These tissues protect against sexually transmitted infections and urinary tract infections. Common infections include urinary tract infections (UTIs), vaginitis, and sexually transmitted infections (STIs), triggering immune responses such as increased antimicrobial peptide production, localized inflammation, and antibody production.

• Mammary gland: The mammary gland produces milk to nourish newborns, providing immune protection through breast milk containing antibodies, immune cells, and antimicrobial factors. Histologically, the mammary gland consists of lobules with alveoli that produce milk during lactation. Mammary glands provide immune protection to newborns through breast milk. Mastitis, an inflammation of the mammary gland, can occur, leading to immune responses such as increased leukocyte infiltration and cytokine production.

Physical, Chemical, and Innate Defenses

• Mucus: Mucus is composed of water, electrolytes, lipids, and glycoproteins known as mucins, secreted by goblet cells in the epithelial lining of mucosal surfaces. The gel-like property of mucus is attributed to the high molecular weight and glycosylation of mucins, which form a cross-linked network that traps pathogens and debris. Mucus is produced by goblet cells, which are specialized epithelial cells found in the respiratory, gastrointestinal, and urogenital tracts. These cells synthesize and secrete mucins, the major structural component of mucus. Mucus acts as a physical barrier by trapping pathogens, preventing them from adhering to and invading the underlying epithelial cells. It also contains antimicrobial substances such as lysozyme, lactoferrin, and IgA antibodies, which help to neutralize and eliminate pathogens. Additionally, mucus facilitates the clearance of trapped pathogens and debris through mucociliary clearance in the respiratory tract and peristalsis in the gastrointestinal tract.

• Gastric acidity: Gastric acidity is maintained by parietal cells in the stomach lining, which secrete hydrochloric acid (HCl). The pH in the stomach typically ranges from 1.5 to 3.5, creating a highly acidic environment that is lethal to many ingested pathogens. Parietal cells secrete HCl via the action of the H+/K+ ATPase pump, which actively transports H+ ions into the stomach lumen in exchange for K+ ions. Gastric acid kills ingested pathogens by denaturing proteins, disrupting cell membranes, and inhibiting the growth and replication of bacteria, viruses, and parasites. It also activates pepsinogen, a zymogen secreted by chief cells, into pepsin, an enzyme that degrades proteins. The acidic environment of the stomach provides a crucial barrier against ingested pathogens, preventing them from colonizing the gastrointestinal tract and causing infection.

• Proteolytic enzymes: Proteolytic enzymes, such as pepsin in the stomach, trypsin and chymotrypsin in the small intestine, and various peptidases, degrade proteins and peptides of pathogens. Pepsin is secreted by chief cells in the stomach as an inactive zymogen called pepsinogen, which is activated by gastric acid. Trypsin and chymotrypsin are secreted by pancreatic acinar cells as inactive zymogens called trypsinogen and chymotrypsinogen, respectively, and are activated in the small intestine. Proteolytic enzymes break down proteins and peptides into smaller fragments, such as amino acids and oligopeptides, by hydrolyzing the peptide bonds between amino acids. By degrading proteins and peptides of pathogens, proteolytic enzymes disrupt their structure and function, leading to their inactivation and elimination. This enzymatic degradation prevents pathogens from adhering to and invading mucosal surfaces and reduces their ability to cause infection.

• Tight junctions between epithelial cells: Tight junctions are multiprotein complexes that form a continuous barrier between epithelial cells, preventing the paracellular passage of pathogens and molecules. Tight junctions are composed of transmembrane proteins such as claudins, occludin, and junction adhesion molecules (JAMs), which interact with intracellular scaffolding proteins such as ZO-1, ZO-2, and ZO-3. These proteins create a physical barrier that seals the intercellular space between epithelial cells, preventing the passage of pathogens, toxins, and antigens. Tight junctions are located at the apical region of epithelial cells, forming a belt-like structure that encircles each cell. They prevent pathogen invasion between cells by blocking the paracellular route, which is the space between adjacent cells. This barrier function is crucial for maintaining the integrity of mucosal surfaces and preventing pathogens from reaching the underlying tissues.

• Defensins produced by Paneth cells: Defensins are small, cationic antimicrobial peptides produced by Paneth cells in the small intestine. These peptides have broad-spectrum antimicrobial activity against bacteria, fungi, and viruses. Paneth cells are specialized epithelial cells located at the base of the crypts of Lieberkühn in the small intestine. They secrete defensins, lysozyme, and other antimicrobial factors in response to microbial stimuli. Defensins insert into the microbial membrane, forming pores that disrupt membrane integrity and lead to cell lysis. They are effective against a wide range of pathogens, including Gram-positive and Gram-negative bacteria, fungi, and enveloped viruses. By killing bacteria, fungi, and viruses, defensins contribute to the maintenance of a healthy gut microbiota and prevent pathogen colonization and invasion.

• Neutrophil recruitment upon PAMP detection: Neutrophils are recruited to mucosal surfaces upon detection of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs). This initiates inflammation and pathogen clearance. PAMPs are molecular motifs found on pathogens that are recognized by PRRs on immune cells. PRRs include Toll-like receptors (TLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs). When PRRs detect PAMPs, they activate intracellular signaling pathways that lead to the production of chemokines and cytokines, such as IL-8 and TNF-α. These chemoattractant molecules recruit neutrophils from the bloodstream to the site of infection. Neutrophils clear pathogens through phagocytosis, degranulation, and the release of reactive oxygen species (ROS). They engulf and destroy pathogens, release antimicrobial substances from granules, and generate ROS to kill microbes. Neutrophil recruitment is therefore essential for initiating inflammation and pathogen clearance at mucosal surfaces.

Mucosal Immunity Overview

• Most pathogens enter the body through mucosal surfaces via ingestion, inhalation, or sexual transmission: The vast majority of pathogens gain entry into the human body through mucosal surfaces, including the gastrointestinal tract, respiratory tract, and urogenital tract. These surfaces are constantly exposed to the external environment and are therefore vulnerable to microbial invasion. Ingestion of contaminated food or water allows pathogens to enter the gastrointestinal tract, leading to infections such as gastroenteritis and food poisoning. Inhalation of airborne pathogens allows them to enter the respiratory tract, causing infections such as pneumonia and influenza. Sexual transmission of pathogens allows them to enter the urogenital tract, leading to sexually transmitted infections such as chlamydia and HIV. Because mucosal surfaces are primary sites of pathogen entry, mucosal immunity is crucial for overall protection against infection.

• The gastrointestinal, respiratory, and genitourinary tracts are highly guarded by immune cells: The gastrointestinal, respiratory, and genitourinary tracts are equipped with a sophisticated network of immune cells and molecules that provide continuous surveillance and rapid responses to invading pathogens. These immune cells include T cells, B cells, macrophages, dendritic cells, and NK cells, which are strategically positioned within the mucosal tissues to detect and eliminate pathogens. These immune cells reside in the lamina propria, which is a layer of connective tissue beneath the epithelial cells, and are organized into specialized structures such as Peyer's patches in the small intestine and tonsils in the upper respiratory tract. They are capable of recognizing a wide range of pathogens and initiating appropriate immune responses to prevent infection.

• These cells reside in the highly vascularized lamina propria beneath the epithelial cells: Immune cells such as T cells, B cells, macrophages, and dendritic cells reside in the lamina propria, which is a layer of connective tissue that lies beneath the epithelial cells lining mucosal surfaces. The lamina propria is highly vascularized, meaning it is rich in blood vessels that facilitate the recruitment of immune cells from the bloodstream to the tissues. The lamina propria also contains lymphatic vessels, which drain fluid and cells from the tissues to the lymph nodes, where immune responses are initiated. The strategic location of immune cells in the lamina propria allows them to efficiently monitor the mucosal surface for signs of infection and respond rapidly to invading pathogens. They can interact with epithelial cells, secrete cytokines and chemokines, and initiate adaptive immune responses to eliminate pathogens and maintain tissue homeostasis.

Lamina Propria

The lamina propria is connective tissue beneath the epithelium, containing the enteric nervous system (myenteric and submucosal plexuses), blood vessels, and immune cells, supporting both immune and non-immune functions. The enteric nervous system, composed of the myenteric and submucosal plexuses, regulates gastrointestinal motility, secretion, and absorption.

Gut-Associated Immunity

• Diffuse collections of T and B lymphocytes, antibody-secreting plasma cells, and phagocytes are present: Diffuse collections of immune cells, including T cells, B cells, plasma cells, and phagocytes, are scattered throughout the lamina propria of the gut mucosa. These cells provide immediate defense capabilities against invading pathogens. T cells include CD4+ helper T cells, which secrete cytokines to activate other immune cells, and CD8+ cytotoxic T cells, which kill infected cells. B cells differentiate into plasma cells, which secrete antibodies, such as IgA, that neutralize pathogens and prevent their adhesion to mucosal surfaces. Phagocytes, such as macrophages and dendritic cells, engulf and destroy pathogens and present antigens to T cells to initiate adaptive immune responses. The presence of these immune cells in the lamina propria ensures a rapid and coordinated response to pathogens.

• Lymphocytes are organized into mucosa-associated lymphoid tissue (MALT) with well-formed follicles: In addition to the diffuse collections of immune cells, lymphocytes are organized into structured lymphoid tissues called mucosa-associated lymphoid tissue (MALT). MALT includes Peyer's patches in the small intestine, isolated lymphoid follicles, and the appendix. These tissues contain well-formed follicles with germinal centers, where B cells undergo somatic hypermutation and affinity maturation, leading to the production of high-affinity antibodies. MALT enhances antigen presentation and lymphocyte activation by bringing immune cells into close proximity with antigens and antigen-presenting cells (APCs). It therefore plays a critical role in initiating and coordinating immune responses in the gut.

• Human MALT includes lingual, palatine, and pharyngeal tonsils, Peyer's patches of the small intestine, and the appendix: Human MALT encompasses various lymphoid tissues located throughout the body, including the tonsils, Peyer's patches, and the appendix. The lingual, palatine, and pharyngeal tonsils are located in the oral cavity and pharynx and provide immune surveillance against inhaled and ingested pathogens. Peyer's patches are organized lymphoid follicles found in the ileum of the small intestine and are responsible for sampling antigens from the gut lumen and initiating immune responses. The appendix is a small, finger-like projection from the cecum that contains lymphoid tissue and contributes to immune surveillance in the large intestine. Each of these MALT components plays a distinct role in protecting against infection.

MALT Examples

• GALT (gut-associated lymphoid tissue): GALT includes Peyer's patches and isolated lymphoid follicles in the small intestine, which sample antigens from the gut lumen and initiate immune responses. Peyer's patches are organized lymphoid follicles located in the ileum and contain M cells, which are specialized epithelial cells that transport antigens from the gut lumen to the underlying lymphoid tissue. Isolated lymphoid follicles are smaller and less organized than Peyer's patches but also contribute to antigen sampling and immune activation.

• NALT (nasopharyngeal-associated lymphoid tissue): NALT includes the tonsils and adenoids in the nasopharynx, which provide immune surveillance against inhaled pathogens. The tonsils and adenoids are strategically located at the entrance of the respiratory tract and contain lymphoid follicles with germinal centers, where B cells undergo somatic hypermutation and affinity maturation. They trap pathogens and antigens and present them to immune cells, initiating immune responses.

• BALT (bronchus-associated lymphoid tissue): BALT is found in the respiratory tract and consists of lymphoid aggregates along the bronchi, providing immune protection against inhaled pathogens. BALT is similar to GALT and NALT in that it contains lymphoid follicles with germinal centers and is involved in antigen sampling and immune activation. It is induced by chronic inflammation or infection in the respiratory tract.

• Urogenital MALT: Urogenital MALT protects the urinary and reproductive systems against sexually transmitted infections and urinary tract infections. It includes lymphoid aggregates in the lamina propria of the bladder, urethra, vagina, and cervix. These tissues contain immune cells that recognize and respond to pathogens, such as bacteria, viruses, and fungi. They produce antibodies and cytokines that neutralize pathogens and recruit other immune cells to the site of infection.

Challenges and Solutions for the Mucosal Immune System

• Challenge: Mucosal surfaces are entry points for many harmful pathogens, yet must remain hypo-responsive to harmless antigens: Mucosal surfaces, such as the gastrointestinal tract and respiratory tract, are constantly exposed to a wide range of antigens, including pathogens, commensal microbes, food antigens, and environmental allergens. While it is essential for the mucosal immune system to mount protective responses against harmful pathogens, it must also remain tolerant to harmless antigens to prevent chronic inflammation and tissue damage. This delicate balance between immunity and tolerance is a major challenge for the mucosal immune system.

• Solution: Complex regulatory mechanisms to balance immunity and tolerance, involving regulatory T cells, IgA antibodies, and dendritic cell subsets: The mucosal immune system employs several regulatory mechanisms to maintain the balance between immunity and tolerance. These mechanisms include the induction of regulatory T cells (Tregs), the production of IgA antibodies, and the differentiation of tolerogenic dendritic cell subsets. Tregs suppress excessive immune responses and promote tolerance to harmless antigens. IgA antibodies neutralize pathogens and prevent their adhesion to mucosal surfaces without causing inflammation. Tolerogenic dendritic cells present antigens to T cells in a way that promotes tolerance rather than immunity. Together, these mechanisms ensure that the mucosal immune system responds appropriately to different types of antigens.

Gut-Associated Lymphoid Tissue (GALT)

GALT is separated from the intestinal lumen by columnar epithelium with tight junctions and a mucous layer, interspersed with micro-fold, or M-cells, providing a physical and immunological barrier. The columnar epithelium with tight junctions prevents the passage of pathogens and antigens, while the mucous layer traps pathogens and facilitates their removal. M-cells sample antigens from the gut lumen and transport them to the underlying lymphoid tissue, initiating immune responses.

M-Cells

M-cells are specialized antigen-transporting cells in Peyer's patches that sample antigens from the gut lumen, initiating immune responses. M-cells differ from other epithelial cells in that they have short, irregular microvilli on their apical surface and lack a thick glycocalyx layer. This allows them to efficiently take up antigens from the gut lumen via endocytosis and transcytosis. They then transport the antigens to the underlying lymphoid tissue, where they are presented to immune cells, such as T cells and B cells.

Role of M-Cells

• M-cells have short, irregular microvilli on their apical surface: M-cells are characterized by their short, irregular microvilli on their apical surface, which increases their surface area for antigen uptake. Unlike neighboring epithelial cells, M-cells do not have a thick glycocalyx layer, which facilitates the binding and uptake of antigens. The short, irregular microvilli and lack of glycocalyx layer allow M-cells to efficiently sample antigens from the gut lumen.

• They endocytose antigens and transport them to the basal surface for lymphocytes, dendritic cells, and macrophages: M-cells take up antigens from the gut lumen via endocytosis, a process in which the cell membrane invaginates and engulfs the antigen. Once inside the M-cell, the antigens are transported to the basal surface in vesicles, where they are released into the extracellular space. From there, the antigens are taken up by lymphocytes, dendritic cells, and macrophages, which then initiate immune responses. This process allows M-cells to efficiently deliver antigens to immune cells and promote immune activation.

Antigen Uptake and Presentation by M Cells

• M cells take up antigen via endocytosis and phagocytosis: M cells utilize endocytosis and phagocytosis to capture a wide range of antigens from the gut lumen. Endocytosis involves the internalization of soluble antigens and small particles, while phagocytosis involves the engulfment of larger particles, such as bacteria and dead cells. These processes are mediated by receptors on the M cell surface that bind to specific ligands on the antigens or particles. Once the antigens are internalized, they are processed and presented to immune cells.

• Antigens are transported across M cells in vesicles and released at the basal surface: After being taken up by M cells, antigens are transported across the cell in vesicles. These vesicles move from the apical surface to the basal surface of the M cell, where they fuse with the cell membrane and release the antigens into the underlying tissue. This process allows antigens to be delivered to immune cells, such as dendritic cells, T cells, and B cells, which can then initiate an immune response.

• Dendritic cells bind antigens and activate T cells: Dendritic cells are specialized antigen-presenting cells that play a critical role in initiating T cell responses. They capture antigens that have been transported across M cells and process them into peptides that can be presented to T cells. Dendritic cells express MHC class I and class II molecules, which bind to the processed peptides and present them to T cells. When T cells recognize the peptide-MHC complexes on dendritic cells, they become activated and initiate an immune response. This involves the production of cytokines, the proliferation of T cells, and the differentiation of T cells into effector cells that can kill infected cells or help B cells produce antibodies.

Alternative Antigen Entry Pathways

Dendritic cells can extend processes across the epithelial layer to capture antigen from the gut lumen directly, providing an alternative route for antigen sampling. This process allows dendritic cells to sample antigens without the need for M cells.

Additional Antigen Entry Pathways

• Transport of antigens by M cells: M cells, as described earlier, are specialized epithelial cells that transport antigens from the gut lumen to the underlying lymphoid tissue. This pathway is particularly important for sampling antigens that are not easily captured by other mechanisms.

• Dendritic cells reaching between epithelial cells directly into the lumen: Dendritic cells can extend processes between epithelial cells to directly capture antigens from the gut lumen. This process involves the migration of dendritic cells towards the epithelial layer and the extension of their processes through the tight junctions that connect epithelial cells. This allows dendritic cells to sample antigens without the need for M cells.

• Uptake of apoptotic epithelial cells: Apoptotic epithelial cells can be taken up by phagocytes, such as macrophages and dendritic cells. This process can lead to the presentation of self-antigens to immune cells, which can help to maintain tolerance.

• Direct access to antigens due to breaks in epithelial integrity: In certain cases, the epithelial barrier may be disrupted due to inflammation, infection, or injury. This can allow antigens to directly access the underlying tissue and activate immune cells. However, this can also lead to excessive inflammation and tissue damage.

T-Cell Activation and Trafficking

• Naive lymphocytes are activated in Peyer's patches: Naive lymphocytes, which have not yet encountered their specific antigen, are activated in Peyer's patches. Peyer's patches are organized lymphoid tissues located in the small intestine that are specialized for sampling antigens from the gut lumen. When naive lymphocytes encounter their specific antigen in Peyer's patches, they become activated and initiate an immune response.

• Effector cells travel via lymph and blood to the lamina propria of the mucosal tissue: After being activated in Peyer's patches, effector cells, which are immune cells that can directly kill infected cells or help B cells produce antibodies, travel via the lymph and blood to the lamina propria of the mucosal tissue. The lamina propria is a layer of connective tissue that lies beneath the epithelial layer of the mucosal tissue. It is the site where immune responses are carried out.

• T cells enter Peyer's patches from blood vessels, directed by homing receptors CCR7 and L-selectin: T cells enter Peyer's patches from blood vessels, directed by homing receptors CCR7 and L-selectin. Homing receptors are molecules on the surface of T cells that allow them to bind to specific molecules on the surface of blood vessels in Peyer's patches. This allows T cells to migrate from the blood into the Peyer's patches.

• Activated T cells drain via mesenteric lymph nodes to the thoracic duct: Activated T cells drain via mesenteric lymph nodes to the thoracic duct, and return to the gut via the bloodstream, ensuring systemic distribution of effector cells. After being activated in Peyer's patches, T cells migrate to the mesenteric lymph nodes, which are located near the small intestine. In the mesenteric lymph nodes, T cells undergo further activation and proliferation. They then drain into the thoracic duct, which is a large lymphatic vessel that empties into the bloodstream. This allows T cells to circulate throughout the body and reach sites of infection or inflammation.

• Activated T cells expressing α4:β7 integrin and CCR9 home to the lamina propria and intestinal epithelium: Activated T cells expressing α4:β7 integrin and CCR9 home to the lamina propria and intestinal epithelium of the small intestine, targeting gut-specific immune responses. α4:β7 integrin and CCR9 are homing receptors that bind to specific molecules on the surface of blood vessels in the lamina propria and intestinal epithelium. This allows T cells to migrate from the blood into these tissues, where they can carry out their effector functions.

Lymphocyte Circulation

Lymphocytes circulate within the mucosal-associated lymphoid system. Antigen-stimulated cells move from Peyer's patches to colonize the lamina propria and other mucosal surfaces, forming a common mucosal immune system.

Peyer's Patches

• Peyer's patches are the site of induction of immune responses in the gut: Peyer's patches are specialized lymphoid tissues in the small intestine that play a crucial role in initiating immune responses against pathogens in the gut lumen. They serve as a primary site where immune cells interact with antigens and become activated to defend against potential threats.

• M-cells take up foreign material, including bacteria, and pass it to APCs in Peyer's patches: M-cells, which are specialized epithelial cells in Peyer's patches, capture foreign materials, such as bacteria, viruses, and other antigens, from the gut lumen. These M-cells then transport the captured antigens to antigen-presenting cells (APCs) within the Peyer's patches, such as dendritic cells and macrophages.

• After activation, lymphocytes travel via lymph to mesenteric lymph nodes: Once lymphocytes are activated in Peyer's patches, they migrate through the lymphatic vessels to the mesenteric lymph nodes. These lymph nodes are strategically located near the small intestine and serve as secondary lymphoid organs where further immune activation and proliferation occur. Lymphocytes undergo clonal expansion and differentiation into effector cells, such as antibody-secreting plasma cells and cytotoxic T lymphocytes, which are essential for eliminating pathogens.

CD103-positive Dendritic Cells

APCs from Peyer's patches, mesenteric lymph nodes, and lamina propria contain CD103-positive dendritic cells, which express retinal dehydrogenase enzymes that convert vitamin A to retinoic acid. CD103-positive dendritic cells are a subset of dendritic cells that play a critical role in regulating immune responses in the gut. They express the integrin αEβ7, also known as CD103, which allows them to interact with epithelial cells and sample antigens from the gut lumen. These dendritic cells also express enzymes that convert vitamin A to retinoic acid, a metabolite that has potent immunomodulatory effects.

Role of Retinoic Acid

Retinoic acid stimulates lymphocytes through retinoic acid receptors (RARs), inducing:

• Upregulation of lymphocyte α4β7 integrin and the CCR9 gut homing receptors: Retinoic acid promotes the expression of gut-homing receptors on lymphocytes, enabling these cells to migrate specifically to the intestinal mucosa. The upregulation of α4β7 integrin and CCR9 is crucial for directing lymphocytes to the gut-associated lymphoid tissues, where they can mount immune responses against pathogens.

• Enhanced differentiation of Foxp3 regulatory T cells: Retinoic acid enhances the differentiation and function of Foxp3 regulatory T cells, which play a pivotal role in suppressing excessive immune responses and maintaining immune tolerance in the gut. These regulatory T cells help prevent the development of inflammatory conditions, such as inflammatory bowel disease, by dampening the activation of autoreactive T cells.

• Favored generation of IgA-producing B cells: Retinoic acid promotes the development of IgA-producing B cells, which are essential for neutralizing pathogens and maintaining immune homeostasis in the gut. IgA antibodies secreted by these B cells are transported across the epithelial barrier and into the gut lumen, where they can bind to pathogens and prevent their attachment to the intestinal mucosa.

Gut-Specific Homing

Gut-specific homing targets activated T cells and antibody-secreting cells to both inflamed and non-inflamed regions of the gut. This process ensures that immune cells are strategically positioned to respond to pathogens and maintain immune surveillance in the gut, regardless of whether