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CHaPTEr 20 Host Defenses at Mucosal Surfaces 287

Mucosal Innate Lymphoid Cells airway branches. Together, GALTs and NALTs in humans and
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ILCs constitute recently described groups of lymphoid cells that GALTs, BALTs, and NALTs in experimental species are termed
are predominantly found in mucosal tissues. ILCs lack T- or mucosa-associated lymphoreticular tissue (MALT).
B-cell receptors. They contribute to innate regulation of homeo- The vast areas of the mucosal immune system characterized
stasis through their ability to rapidly produce cytokines. Similar by diffuse collections of lymphoid cells are termed effector tissues.
to CD4 T helper (Th) cells (Chapter 16), ILCs can be divided These include the interstitial tissues of the mammary, lacrimal,
4,5
into three major groups according to cytokines they produce. salivary, sweat, and all other exocrine glands, as well as the lamina
Group 1 ILCs (ILC1) produce interferon-γ (IFN-γ) and are propria and the epithelium of the GI tract. The lamina propria
considered similar to Th1 cells. Cells with ILC1 phenotypes areas of the upper respiratory and genitourinary tracts are also
express CD103/CD160 and CD127 and include NK cells, which lymphoid effector sites. MALT is connected with effector sites
are large granular lymphocytes found in the lamina propria and through the migratory patterns of effector cells.
the intraepithelial compartment. Group 2 ILCs are similar to
Th2 cells and produce IL-5, IL-9, IL-13, and amphiregulin. ILC2
are responsible for innate responses in allergies and asthma. As KEY CONCEPTS
with Th17 cells, group 3 ILCs (ILC3) secrete IL-17 and/or IL-22. The Common Mucosal Immune System
Although lymphoid tissue inducer (LTi) cells are ILC3, functional
properties of these cells are distinct from other mucosal ILC3. 4,5 The term mucosa-associated lymphoreticular tissue (MALT) comprises
discrete and diffuse collections of lymphoid tissues that share distinctive
Two types of ILC1 occur in tonsils and the mucosa of the GI features, including a unique type of epithelium, a distinct architecture,
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tract. CD103 CD160 ILCs are found in the intraepithelium of a unique set of antigen-presenting cells (APCs), and B cells, where
the intestines and produce perforin and granzyme like NK cells. switching to immunoglobulin A (IgA) predominates. The involved tissues
This ILC1 subset requires Nfil3 and T-bet transcription factors include:
for its development. An ILC1 population expressing low levels • Gut-associated lymphoid tissues (GALTs): Peyer patches (PPs), the
of RORγt and aryl hydrocarbon receptor (Ahr) similar to ILC3 appendix, and solitary lymphoid nodules in the gastrointestinal (GI)
tract
was identified in humans. These ILCs express IL-7Rα (CD127), • Nasal-associated lymphoid tissues (NALTs): tonsils and adenoids
but not conventional lymphocyte lineage or NK cell markers. • Effector tissues: the interstitial tissues of the mammary, lacrimal,
Both subsets of ILC1 may be involved in the induction of inflam- salivary, sweat, and all other exocrine glands; the lamina propria and
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matory bowel disease (IBD). ILC2 are seen in the lungs, upper the epithelium of the GI tract; and the lamina propria areas of the
respiratory mucosa, gut, and skin. By producing IL-5, IL-13, and upper respiratory and genitourinary tracts.
amphiregulin, they play key roles in the clearance of parasites,
including Nippostrongylus brasiliensis and Trichuris muris. ILC2
are also important in the development of asthma and allergies, MALT as an Inductive Site
including atopic dermatitis. Although ILC2 were reported to MALT has a unique type of epithelium for antigen uptake. Its
promote airway hypersensitivity during acute influenza virus features include a characteristic architecture, antigen-presenting–
infection, the amphiregulin they produce could also help maintain cell (APC) and B cell areas with germinal centers where switches
lung epithelial cell homeostasis. 4 to IgA predominate. The columnar epithelium that covers MALT
ILC3 in both humans and mice showed heterogenic cytokine is infiltrated with lymphocytes and APCs, leading to the term
profiles. Thus human ILC3 bearing NKp44 and CCR6 produce follicle-associated epithelium (FAE). Lacking goblet cells, the
IL-22 alone. However, human ILC3 isolated from patients with FAE is covered with far less mucus than normal enterocytes.
Crohn disease produce IL-17 and IFN-γ. Mouse LTi and LTi-like Soluble and particulate luminal antigens are taken up by microfold
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ILC3 produce both IL-17 and IL-22. NKp46 ILC3 secrete IL-22, (M) cells and are delivered to adjacent APCs. M cells have been
as well as IFN-γ under certain conditions, but not IL-17. Another described in PPs, the appendix, and tonsils and represent 10–15%
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subset of mouse ILC3 that produces IFN-γ, IL-17, and IL-22 can of cells within the FAE. M cells are also found in isolated
be found in the large intestine. ILC3-derived IL-22 induces lymphoid follicles (ILFs) and at the tips of the villus, where they
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antimicrobial peptide responses by intestinal epithelial cells (IECs). are termed villous M cells. The microvilli of these cells, which
Furthermore, IL-22 from ILC3 was reported to enhance innate are less dense than those of adjacent enterocytes, offer a portal
immunity against Salmonella and bacterial infection secondary of entry into MALT (Fig. 20.2). The M cell is often identified
4,5
to influenza virus infection. Since ILC3 are also involved in by an invagination of the basolateral membrane into a “pocket”
the induction of colonic inflammation and colorectal cancer, normally occupied by lymphocytes and APCs (Fig. 20.3).
they may act as a double-edged sword in the mucosal immune M cells appear ideal for antigen uptake owing to a well-
system. 4,5 developed microvesicle system that contains endosomes. However,
it remains unclear whether M cells act as classic APCs. M cells
A COMMON MUCOSAL ADAPTIVE also provide a portal of entry for some pathogens, such as invasive
IMMUNE SYSTEM strains of Salmonella typhimurium, but not for noninvasive strains
of S. typhimurium and reoviruses.
Higher-order mammals have developed an organized secondary
lymphoid tissue system in the GI and upper respiratory tracts. Gut-Associated Lymphoreticular Tissues
Gut-associated lymphoreticular tissues (GALTs) include Peyer Each PP contains a dome region that is positioned under the
patches (PPs), the appendix, and solitary lymphoid nodules in FAE. This dome region is populated by T cells, B cells, macro-
the GI tract (Chapter 2). Tonsils and adenoids comprise nasal- phages (MØs), and dendritic cells (DCs). It includes follicles
associated lymphoid tissues (NALTs). Experimental animals, such that contain germinal centers. The presence of all three major
as rabbits, rats, and guinea pigs, exhibit organized bronchus- APC types in the dome (i.e., memory B cells, MØs, and DCs)
associated lymphoid tissues (BALTs) that rarely occur in human makes it likely that antigen uptake occurs immediately following