Page 183 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 10 Chemokines and Chemokine Receptors 165

effector T-cell trafficking. Pathogens can skew the nature and to move from the T zone following activation to the follicles
magnitude of the immune response in a specific direction by where they provide help for B-cell maturation and antibody
means of specific pattern recognition receptor (PRR) ligands. production. Reciprocally, B cells activated by antigen in the follicles
The chemokine receptors expressed on DCs vary, depending upregulate CCR7 and move toward the T-cell zone. Thus B–T
on the nature of the inflammatory stimulus and type. For interaction can be facilitated by the reciprocal movement of
example, blood-derived plasmacytoid and myeloid DCs express these cells, which may be influenced by the balance of chemokines
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a similar repertoire of inflammatory chemoattractant receptors, made in adjacent lymphoid zones. CXCR4 signaling is also
but they are functional only on myeloid DCs. CCL3, CCL4, important in naïve and memory B-cell trafficking to germinal
and CCL5 may be particularly important for recruiting additional centers. CCR5 ligands can guide naïve CD8 T cells to sites of
mononuclear phagocytes and DCs to sites of infection. This CD4 T cell–DC interaction in lymph nodes.
can amplify the late stage of the innate immune response. In
the extreme, this can devolve into endotoxic shock. Consistent Efferent Trafficking
with this idea, genetic disruption of the CCL3/CCL4/CCL5 Naïve lymphocytes that do not encounter antigen continue to
receptor CCR5 renders mice relatively resistant to LPS-induced recirculate between blood and secondary lymphoid tissue without
endotoxemia. acquiring any tissue-specific homing properties. Most antigen-
stimulated T cells die by apoptosis. The survivors can be divided
Adaptive Immunity into functionally distinct subsets marked by characteristic patterns
Afferent Trafficking to Secondary Lymphoid Tissue of chemokine receptor expression. In general, the trafficking
The homeostatic receptors CXCR5 and CCR7 and their ligands properties of these cells are not well understood.
are major regulators of the immune response. They act at the Among CD4 T cells, three memory subsets and two main
level of B and T lymphocytes and DCs trafficking to and within effector subsets have been proposed. The memory subsets include
secondary lymphoid tissue. 21,22 DC maturation in peripheral T FH cells described above as well as effector memory cells (T EM ),
tissues is associated with downregulation of inflammatory central memory cells (T CM ), and tissue resident memory cells
receptors, which is important for recruitment, migration, and (T RM ). T EM do not express l-selectin or CCR7. They traffic
retention in the periphery, and reciprocal upregulation of CCR7, through peripheral tissues as immune surveillance cells, rapidly
which mediates mature DC migration to draining lymph nodes. releasing cytokines in response to activation by recall antigens.
Inflammatory receptors, such as CCR2, may also contribute to T CM cells express CCR7 and lymph node homing receptors.
afferent trafficking. CCR7 is also a major lymph node trafficking They traffic between blood and secondary lymphoid organs
receptor for naïve T cells and can mediate activated T-cell exit but are not polarized and lack immediate effector function.
from inflamed tissue. Instead, they efficiently interact with DCs in the lymph node
The CCR7 ligand CCL21 is constitutively expressed on afferent and differentiate into effector cells upon secondary stimulation.
lymphatic endothelium, high endothelial venules (HEVs), stromal Highly heterogeneous, multifunctional human T EM cells are
cells, and interdigitating DCs in the T zones of the lymph node, produced early in differentiation and may become stable resting
Peyer patch, mucosa-associated lymphoreticular tissue, and cells. 24
8
spleen. It is not expressed in B-cell zones or sinuses. CCL19, Upon antigen activation, the classic effector CD4 T-cell subsets,
another CCR7 ligand, is also restricted to the T-cell zone and is Th1, Th2, and Th17, downregulate CCR7 and upregulate inflam-
expressed on interdigitating DCs. matory chemokine receptors. Exit from lymph node via efferent
−/−
CCR7 mice and the plt mouse, which is naturally deficient lymphatics is mediated by additional mechanisms, including
in CCL19 and a CCL21 isoform expressed in secondary lymphoid S1P1 (sphingosine 1 phosphate type 1 receptor) signaling, which
organs, have similar phenotypes: atrophic T-cell zones populated can be blocked by the drug FTY720. In vivo, Th1 cells more
by a paucity of naïve T cells. This and the failure of activated frequently express CXCR3, CXCR6, CCR2, CCR5, and CX3CR1
DCs to migrate to the lymph node from the skin of these mice than do Th2 cells, and the pattern of receptor expression is a
25
explain why contact sensitivity, delayed type hypersensitivity, function of maturation and age. In contrast, Th2 cells more
and antibody production are severely impaired. However, lymph frequently express CCR3, CCR4, and CCR8 than do Th1 cells.
node trafficking is not completely abolished in these mice, which CXCR3 expression has been most consistently associated with
may develop autoimmune phenomena. Th1 immune responses and Th1-associated diseases. Its agonists
CXCR5 is expressed on all peripheral blood and lymph node CXCL9-11 are highly induced by IFN-γ but not IL-4. “Th1
B cells as well as on some T cells. Its ligand, CXCL13, is expressed chemokines” help maintain Th1 dominance through their ability
constitutively on follicular HEVs and controls trafficking of to block CCR3. Similarly, in Th2 immunity, IL-4 and IL-13 made
CXCR5 positive B and T cells from blood into the follicles. In at inflamed sites in the periphery induce production of CCL7,
−/−
CXCR5 mice, B cells do not migrate to the lymph node, Peyer CCL11 and other CCR3 ligands, the CCR4 ligands CCL17 and
patches are abnormal, and inguinal lymph nodes are absent. CCL22, and the CCR8 ligands CCL1 and, in the mouse, CCL8.
CXCL13 is also required for B1 cell homing, natural antibody CCR3 is expressed on a subset of Th2 lymphocytes as well as
−/−
production, and body cavity immunity. CXCR5 mice still can on eosinophils and basophils, the three major cell types associated
produce antibody, perhaps, in part, because B cells and follicular with Th2-type allergic inflammation. Th2 cells are also associated
DCs can form ectopic germinal centers within T-cell zones of with CCR4 expression. Arrival of Th2 cells amplifies a positive
the periarteriolar lymphocyte sheath of spleen. feedback loop through secretion of additional IL-4. CCL7 and
CCL11 can block Th1 responses by antagonizing CCR2, CXCR3,
Migration Within Lymph Node Microenvironments and CCR5. Th17 cells are all found within the CCR6 subset of
+
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CXCR5 is expressed on a majority of memory CD4 T cells in CD4 T cells. There may also be a positive feedback loop for
the follicles of inflamed tonsils. T-follicular helper cells (T FH), a IL-17 induction of the CCR6 ligand CCL20 as a mechanism to
+
+
CD57 subset of CXCR5 T cells, lack CCR7, which licenses them recruit additional Th17 cells to inflamed sites.