Page 60 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 3 Innate Immunity 45

has proven difficult. NKT cells express perforin and granulysin TCR repertoire. IELs in the small intestine frequently express of
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and are capable of cytotoxic activity. NKT cells are also able to CD8 αα (CD4 CD8 αα or CD8 αβCD8 αα), a characteristic
influence innate and adaptive immune responses through release of activated mucosal T cells within the gut microenvironment.
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of large amounts of cytokines, including IFN-γ, TNF-α, IL-4, Upon antigenic stimulation, CD8 αβTCRαβ IELs are cytolytic
IL-13, IL-10, and granulocyte macrophage–colony-stimulating and kill via granzymes and perforin or through engagement
factor (GM-CSF). In general, NKTs found in blood can produce of Fas. 40
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large amounts of cytokines, whereas NKTs in the thymus are TCRγδ IELs emigrate from the thymus and subsequently
poor cytokine producers. take up residence in the intestinal epithelium. They constitute
Decreased NKT cell frequency and/or function may increase roughly 10% of intestinal IELs in humans, and the majority
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susceptibility to some autoimmune diseases, including type 1 expresses CD8αα. TCRγδ IELs recognize nonclassic MHC
diabetes (Chapter 71) and multiple sclerosis (Chapter 66). Mice molecules, such as thymus leukemia antigen or MHC class I-like
with NKT defects are susceptible to tumors and adoptive transfer molecules, MICA (MHC I-related chain [MIC]-A) and MICB,
of normal NKTs can provide protection against tumors (Chapter and may help modulate inflammatory immune responses. These
77). NKT cells may also contribute to the pathogenesis of the IELs can be cytolytic and express FasL. TCRγδ+ IELs can produce
airway hyperresponsiveness (AHR) in asthma (Chapter 72), which keratinocyte growth factor and promote intestinal epithelial
is dependent on IL-4 and IL-13 production in the airways. iNKT integrity. 40
cells are necessary for AHR in several murine models of asthma, The B1 and marginal zone (MZ) subsets of B lymphocytes
since NKT-deficient mice fail to develop AHR following allergen have been characterized as innate-like B cells. They express antigen
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challenge, ozone challenge, or viral infection. iNKT cell deficiency receptors enriched for germline sequence. These cell types have
was associated with severe varicella infection, demonstrating a been mostly studied in mice. Their identity in humans is less
role for iNKT cells in innate antiviral immunity. 36 clear. B1 cells and MZ B cells can function as APCs, but unlike
conventional B cells, B1 cells and MZ B cells do not develop
Intraepithelial Lymphocytes, Innate Lymphoid Cells, B1 into memory B cells. B1 cells and MZ B cells share characteristics:
and MZ B Cells, and Mast Cells (i) they are the main source of natural antibodies; (ii) they express
Barrier epithelia of skin and the GI tract contain specific types high surface levels of IgM and low surface levels of IgD; and
of lymphocytes, including intraepithelial T lymphocytes (IELs) (iii) they are rapidly activated by microbes through pattern
and B1 B cells (Chapter 7), which respond to commonly encoun- recognition receptors to produce large amounts of natural
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tered microbes. Because of their more limited diversity of antibodies. B1 cells and MZ B cells produce IL-10 upon activa-
receptors, IELs can be considered part of the innate immune tion, which may downregulate immune responses. The natural
system. The main immune cell populations within the epidermal antibodies produced by B1 cells and MZ B cells function as the
layer include keratinocytes, melanocytes, a type of DC known first line of defense against invading microbes.
as the Langerhans cell, and IELs (Chapter 19). Innate lymphoid cells (ILCs) are a heterogeneous population
Keratinocytes and melanocytes express a variety of PRRs, of cells that have been recently recognized. ILCs do not express
enabling detection of microbes, resulting in secretion of cytokines rearranged antigen-specific receptors. This lymphoid subset
that can contribute to innate immune responses through recruit- includes killer ILCs (e.g., NK cells) and helper ILCs. Helper ILCs
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ment and activation of phagocytes. Langerhans cells form an are further classified as ILC1, ILC2, and ILC3.
elaborate network of dendritic processes that allow them to ILC1 cells express T-bet, similar to NK cells, and produce
capture antigens that gain access to skin. Following activation IFN-γ but lack cytolytic activity. They are found mainly within
by microbes, Langerhans cells migrate to draining lymph nodes tissues and are barely detectable in peripheral blood. Oncogene-
and express chemokine receptor-7 (CCR7), which allows them induced murine cancer model studies suggest that ILC1 cells
to migrate to the T-cell zones within lymph nodes in response may play a role in cancer immunosurveillance. 42
to the chemokine ligands (CCL)-19 and CCL-21 and present ILC2 development is dependent on expression of the transcrip-
antigen to T cells. 38 tion factor GATA-3 and produces the cytokines IL-5 and IL-13.
Intraepidermal T lymphocytes constitute roughly 2% of ILC2 cells were first identified in mice as a source of T helper
lymphocytes within the skin. This lymphocyte subset expresses (Th)2 cytokines (IL-4, -5, -13). ILC2 cells may play a role in
a more restricted set of antigen receptors, which include both antihelmintic immunity, immune surveillance, immune regula-
αβ and γδ TCRs, similar to IELs found in the intestines. These tion, and wound healing. ILC2 cells have been shown to accu-
specialized T cells appear to be committed to recognizing mulate in the skin of patients with AD and within nasal polyps
microbial peptide antigens commonly found at epithelial surfaces of patients with chronic rhinosinusitis. ILC2 cells produce IL-4,
and thus function as components of the innate immune system. 39 -5, and -13 in response to epithelial-derived IL-33, IL-25, and
IELs are a significant component of the GI immune system thymic stromal lymphopoietin (TSLP). The production of Th2
and reside at the basolateral side of the intestinal epithelial cell cytokines by ILC2 cells may represent an early step in the develop-
layer (Chapter 2). IEL are among the first immune cells to ment of atopic disorders. 43
encounter pathogens that have breached intestinal epithelia. IEL ILC3 cells express the retinoic acid receptor related orphan
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consist of CD8 T cells, as well as memory-effector T cells bearing receptor γt (RORγt) and produce IL-17 and IL-22 (Fig. 3.3).
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αβ or γδ TCRs. IELs contain a greater proportion of TCRγδ ILC3 cells include fetal lymphoid tissue inducer (LTi) cells, which
cells than is found in the peripheral circulation. 40 drive secondary lymphoid organ development during embryo-
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CD4 TCRαβ and CD8 αβTCRαβ IELs are class II and class genesis. LTi cells can induce upregulation of adhesion molecules
I restricted, respectively. These IELs have likely undergone thymic on stromal cells and the release of chemokines involved in the
selection and subsequently homed to the gut after antigenic recruitment of T and B lymphocytes and DCs to lymph nodes,
stimulation. As such, these IELs are likely specific for foreign leading to subsequent differentiation of naïve T cells into effector
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antigens. They have a memory phenotype and an oligoclonal T cells and B-cell activation and production of antibody-secreting