Page 310 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 20 Host Defenses at Mucosal Surfaces 291

binding to MAdCAM-1, which is expressed on HEVs in PPs by increased expression of P-selectin ligand on peripheral blood
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and gut LPVs (see Fig. 20.5). The C-type lectins—L-, E-, CD4 and CD8 T cells. As the cells accumulate in the bron-
and P-selectins (Chapter 11)—also serve as homing receptors. choalveolar lavage (BAL) fluid, the number of cells that express
For example, L-selectin can bind to carbohydrate-decorated P-selectin ligand in blood declines. Very late antigen-4 (VLA-4)
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MAdCAM-1 and is an important initial receptor for homing into appears to be involved, as migration of VLA-4 T cells into BAL
GALT HEVs. fluid is impaired following treatment with anti-α 4 antibody.
Chemokines (Chapter 10) are also involved in immune-cell Following systemic immunization, most NALT effector B cells
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homing in mucosal tissues. For example, loss of secondary express L-selectin, with only a few cells expressing α 4 β 7 . Effector
lymphoid tissue chemokine (SLC) results in lack of naïve T-cell B cells induced by nasal immunization display a more promiscu-
or DC migration into the spleen or PPs. Conversely, memory ous pattern of adhesion molecules, with a large majority expressing
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α 4 β 7 T cells that express the receptor for thymus-expressed both L-selectin and α 4 β 7 .
chemokine (TECK), CCR9, migrate into the lamina propria of
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the GI tract. Both human α E β 7 and α 4 β 7 CD8 T cells express The Common Mucosal Immune System Revisited
CCR9, suggesting that TECK-CCR9 is also involved in lymphocyte The homing pattern that has been elucidated in the GI tract
homing and the arrest of IELs in the GI tract epithelium (see after immunization of GALTs has been the model for all mucosal
Fig. 20.4) (Chapters 10, 11). immune sites. As summarized above, the specific set of homing
PPs and GALTs contain both naïve and memory T- and B-cell receptors and ligand addressins expressed in the GI tract are
subsets, whereas the lamina propria consists of memory T and absent in NALTs and associated lymph nodes. It remains pos-
B cells and terminally differentiated plasma cells (see Table 20.1 sible, and even likely, that memory lymphocytes from the gut
and Fig. 20.4). Naïve lymphocytes destined for GALTs express may enter NALTs for additional priming and reprogramming
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L-selectin, moderate levels of α 4 β 7 (α 4 β 7 ) and lymphocyte of homing receptors. Likewise, memory lymphocytes induced
function–associated antigen-1 (LFA-1). Memory lymphocytes in NALTs may traffic to lung and genitourinary tract tissues
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destined for lamina propria express higher levels of α 4 β 7 (α 4 β 7 ) as well as to the GI tract. Thus the rules for the homing of
and lack L-selectin. Initial rolling is dependent on α 4 β 7 interac- naïve lymphocytes precursors to NALTs need to be more
tions with LPV MAdCAM-1. Activation-dependent binding and clearly defined.
extravasation require LFA-1–ICAM binding. α 4 β 7 also mediates
binding to E-cadherin, and CCR9 expression can result in INDUCTION OF MUCOSAL IMMUNITY
activation-dependent entry into the epithelial cell compartment.
Cryosections of human tissues have revealed naïve lymphocytes Mucosal Immune responses are typified by SIgA antibodies, the
in HEVs that express both L-selectin and α 4 β 7 , whereas memory predominant Ig isotype in external secretions. The resistance of
lymphocytes in efferent lymphatics express α 4 β 7 , but not L-selectin. SIgA to endogenous proteases makes them uniquely suited to
The majority of cells in mesenteric lymph nodes, including B-cell protect mucosal surfaces. The development of mucosal adaptive
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blasts, tend to be of the memory phenotype and are α 4 β 7 , immunity requires cytokine signals from CD4, as well as from
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L-selectin . Ig-containing B-cell blasts also express high levels CD8, T cells; DCs, MØs, and B cells; and nonclassic APCs (e.g.,
of α 4 β 7 . This separation of naïve and memory T and B cells for epithelial cells). B cell commitment (Cµ to Cα switching) and
entry into GALT HEVs or LPVs has important implications in B-/T-cell interactions are of central importance for induction
vaccine development (Chapter 90). of pIgA-producing cells.
An oral cholera vaccine was reported to elicit transient IgA
antibody-forming cells (AFCs) in blood and subsequent IgA Mucosal Antigen-Presenting Cells
anticholera toxin AFCs in duodenal tissues. 15,16 In a separate Large macromolecules are taken up by M cells in the GI tract.
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study, peripheral blood AFCs induced after parenteral immuniza- N418 , 2A1 , NLDC-145 , M342 DCs form a dense layer of
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tion were L-selectin , whereas those induced after oral and rectal cells in the subepithelial dome (SED) just beneath the follicle
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immunization were predominantly α 4β 7 AFCs. 15,16 In the latter epithelium, where CD4 T cells can be found, whereas N418 ,
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study, most of the AFCs produced IgA, but some also expressed 2A1 , NLDC-145 , and M342 DCs populate the interfollicular
IgG. After nasal immunization, AFCs expressed both L-selectin T-cell regions, where both CD4 and CD8 T cells reside. DCs in
and α 4 β 7 homing receptors. The APCs in GALTs were shown to the dome region are immature, highly endocytic, and express
produce high levels of retinoic acid, which promotes expression low levels of major histocompatibility complex (MHC) (Chapter
of α 4 β 7 . Thus enteric immunization of GALTs more effectively 5) and B7 molecules. DCs in the T-cell area are mature, with
triggers α 4 β 7 memory IgA and IgG B cells, which can then migrate low endocytic activity and high levels of MHC class I and II
into the bloodstream. molecules and B7 molecule expression (see Fig. 20.4A). DCs are
also found in NALTs, where they play essentially the same role as
Lymphocyte Homing in NALTs and in GALTs.
Lung-Associated Tissues IECs express MHC class II and class I molecules and present
Unlike PP HEVs, which are found in T-cell zones, murine NALT peptides to primed CD4 and CD8 T cells. Human and murine
HEVs are found in B-cell zones and express PNAd, either alone IECs also express CD1d, a nonclassic MHC class I molecule
or associated with MAdCAM-1. Moreover, anti–L-selectin involved in the presentation of lipid and glycolipid antigens
antibodies—but not anti–MAdCAM-1 antibodies—block the (Chapter 5).
binding of naïve lymphocytes to NALT HEVs, suggesting a role
for L-selectin and PNAd in the binding of naïve lymphocytes CD4 T-Helper Cell Subsets in Mucosal Immunity
to these HEVs. 17 Th cells are classified as Th1, Th2, Th17, regulatory T cells
During pulmonary immune responses, induction of VCAM-1, (Tregs), or follicular Th (Tfh) cells according to the cytokines
E-selectin, and P-selectin in the pulmonary vasculature is matched they produce (Chapter 16). Th1 cells produce IFN-γ, LT-α,