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Chapter 13 Chemokines and Hematopoietic Cell Trafficking 139

interstitial tissue may be supported by GAGs, which immobilize The first step in the homing cascade in LNs is mediated by
chemokines and, thus, determine the position and temporal persis- L-selectin/CD62L expressed on all lymphocytes, except effector/
tence of chemokine gradients. 97,98 It has been shown that immobilized, memory cells. PNAd, an O-linked sulfated core 1 carbohydrate
substrate-bound chemokines are effective in inducing directed leuko- moiety that is exclusively found in HEVs, is the major endothelial
99
cyte migration, which is called haptotaxis. It has also been suggested L-selectin ligand. 122–126 Binding of L-selectin to PNAd initiates
that efficient development of tissue chemokine gradients also requires, lymphocyte rolling in HEVs and slows down and marginates the
in addition to the free diffusion of chemokines from their cellular free-flowing lymphocytes. 2,65,125 While the L-selectin–PNAd interac-
sources, scavenging of chemokines by their atypical chemokine recep- tion is required, it is not by itself sufficient to promote firm leukocyte
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tors expressed by cells in apposition to chemokine sources. Leuko- adhesion. The subsequent firm arrest of rolling T and B lymphocytes
cytes moving within the interstitial tissue receive signals from is mediated by the α4ß1 integrin, β2-integrin CD11a/CD18 (LFA-
neighboring cells as well as from the extracellular matrix, activate 1), CD11b/CD18 (Mac-1), and β7-integrin, which bind ICAMs, in
intracellular processes, release inflammatory mediators, and upregu- particular ICAM-1 and ICAM-2, VCAM-1, or MAdCAM-1 on high
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late adhesion molecules and release enzymes. Although neutrophils endothelial cells. 125–130
display enhanced expression of β1-integrins upon transmigration, it Chemokines that are presented in the lumen of HEV function as
remains unclear whether integrins are relevant for interstitial leuko- triggers of integrin activation. 131,132 On naive T cells integrin activa-
cyte migration. According to this, the involvement of integrins seems tion is primarily mediated by CCL21 (previously known as SLC,
to be rather different in 2D versus 3D settings. In contrast to 2D TCA4, exodus 2, or 6-C-kine), which is constitutively expressed and
migration, the 3D tissue network confines and mechanically anchors secreted by HEVs. The secreted chemokine is noncovalently bound
cells from all sides so that they intercalate alongside and perpendicular to GAGs on the surface of HEVs. Here it activates rolling lympho-
to tissue structures. Importantly, 2D but not 3D leukocyte migration cytes through binding to CCR7, which is expressed on naive B and
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seems to be integrin dependent. In this context, proteolytic enzymes T cells. Another CCR7 ligand, CCL19 (previously termed ELC or
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(proteases) such as heparase, elastase, and matrix metalloproteinases MIP3β), also supports T-cell homing to LNs. CCL19 is not
(MMP-2 and MMP-9) provide for degradation of the components expressed by high endothelial cells themselves. However, CCL19 and
of the basement membrane and the ECM, and thus play an important other chemokines may be released by extravascular cells in LNs or in
role in leukocyte interstitial migration. 52,103 tissues that discharge lymph to a local LN. Lymph-borne chemokines
All consecutively occurring steps of (1) leukocyte tethering and can be transported to the luminal aspect of HEVs. Correspondingly,
rolling, (2) exposure to a chemotactic stimulus, (3) firm arrest, (4) chemokines, including CCL2, CCL19, and CCL21, injected under
postadhesive strengthening and intraluminal crawling, (5) diapedesis, the skin of mice accumulate on the luminal surface of the HEV in
and (6) interstitial migration are essential for leukocytes to migrate draining LNs, where they promote integrin activation on rolling
to sites of inflammation. Accordingly, genetic defects in any of the leukocytes bearing the cognate receptors. 133–135 In this context,
molecules involved in either step lead to compromised host defenses. endothelial heparan sulfate has been shown to be essential for control-
Patients with leukocyte adhesion deficiency (LAD) syndrome may ling chemokine presentation on the endothelium and thereby for
have a genetic defect in β2 integrins (type 1) or in fucosylated selectin recruitment of lymphocytes and DCs to lymph nodes. 136
ligands (type 2), and neutrophils either cannot stop or cannot roll, B cells use largely the same trafficking molecules as naive T
respectively. 104–106 Type 3 LAD involves the deficiency of kindlin-3, cells to home to LN. However, B-cell–HEV interactions are only
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a molecule regulating integrin activation and leukocyte adhesion moderately affected by the absence of CCR7 or its ligands. Cor-
reinforcement. 107,108 LAD syndrome is characterized by marked leu- respondingly, LNs of mice lacking CCR7 contain few T cells, while
kocytosis and frequent and severe soft-tissue infections. the B-cell compartment (and the memory T-cell compartment) is less
affected. 138,139 Similar observations were made in plt/plt mice, which
Chemokine Control of Lymphocyte Homing to have a spontaneous genetic defect resulting in deletion of CCL19
and the HEV-expressed form of CCL21 (mice, unlike humans,
Secondary Lymphoid Organs have a second ccl21 gene that is only expressed in lymph vessels
of peripheral tissues), demonstrating that B cells are not absolutely
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Migration of blood-borne lymphocytes to secondary lymphoid dependent on CCR7 to adhere to HEVs. In fact, rolling B cells
organs is the best-characterized example of leukocyte trafficking from can be induced to arrest in HEVs by either CCR7 agonists or by
the circulation into distinct target tissues. 2,4,109–114 Lymphocytes CXCL12 (previously called stromal cell–derived factor [SDF-1]α), the
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constantly survey secondary lymphoid organs, which include the ligand for CXCR4. An additional chemokine pathway involving
spleen, tonsils, appendix, PPs, and LNs. Such homing allows lym- CXCL13 (also called BLC) and its receptor CXCR5 has also been
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phocytes to encounter antigen that may pose a threat to the organism. implicated in B-cell homing to secondary lymphoid tissues. Of
Antigens are collected and presented to T cells by DCs, in conjunc- note, although B cells encounter several distinct integrin-activation
tion with signals by costimulatory molecules and cytokines. In con- signals in HEVs, B-cell homing to LNs is nonetheless less efficient
trast to the spleen, where the molecular mechanisms of leukocyte than that of T cells. A likely reason is that the B cells express only
homing are still are not entirely clear and differ from all other lym- approximately half the number of L-selectin molecules expressed on T
phoid organs, the rules that govern homing of immune cells to LNs cells, which greatly affects their ability to initiate the adhesion cascade
are well understood. Mature DCs, which have acquired antigen in in HEVs. 121,142
peripheral tissues, and some memory cells reach the LNs through The requirement for a sequence of distinct molecular steps that
afferent lymph vessels. 115–117 In contrast, circulating T and B lympho- each leukocyte must undergo to arrest within microvessels explains
cytes gain access to LNs and PPs through specialized postcapillary why only certain leukocyte subsets gain access to lymphoid tissues,
microvessels lined with cuboid endothelial cells that are known as while others are excluded. Granulocytes, for example, express LFA-1
high endothelial venules (HEVs). 118–121 HEVs in different secondary and L-selectin, but not CCR7. Consequently, although granulocytes
lymphoid organs express distinct patterns of trafficking molecules to can roll in HEVs (via L-selectin), these leukocytes do not perceive an
serve as tethering platforms for defined subsets of lymphocytes. For integrin-activating stimulus and, therefore, fail to accumulate in LNs
example, HEVs in LNs express PNAd, whereas HEVs in PPs express or PPs. Likewise, mature DCs express CCR7 and CD11a/CD18, but
mucosal addressin-cell adhesion molecule (MAdCAM-1). Other not L-selectin. Because these cells are thus incapable of rolling in
mucosa-associated lymphoid organs, such as mesenteric LNs, express HEVs, they fail to home to noninflamed LNs from the blood
both MAdCAM-1 and PNAd. Although T and B lymphocytes are (although mature DCs readily access LNs via afferent lymph). Hence,
recruited by similar multistep cascades to home to secondary lym- the GPCR-mediated integration activation step is critical for impart-
phoid organs, the roles of individual traffic molecules are not neces- ing specificity to the process of lymphocyte homing to LN.
sarily identical, even when both subsets interact with the same In HEVs of PPs, similar homing mechanisms are encountered as
microvessel. 2 described earlier for LNs. However, the levels of L-selectin ligands