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176 ParT ONE Principles of Immune Response

tissues by mediating leukocyte tethering and rolling of firm adhesion between leukocytes and endothelial cells. However,
endothelium-bound leukocytes by binding to P-selectin glyco- in specific low-shear conditions, they can also participate in
protein ligand-1 (PSGL-1). rolling. For leukocyte trafficking, the most important integrins
E-selectin and P-selectin are inflammation-inducible molecules. are α 4 β 7 , leukocyte function–associated antigen-1 (LFA-1), and
Within minutes, P-selectin can be translocated from intracellular α 4 β 1 .
storage granules onto the endothelial cell surface, where it binds α 4 β 7 is a principal homing receptor for lymphocyte trafficking
to its leukocyte receptor, PSGL-1 (see Fig. 11.5). P-selectin and to mucosa-associated lymphatic tissues. It binds to MAdCAM-1
PSGL-1 mediate rolling at early time points during inflammation. on HEVs in organized mucosal lymphatic tissues, such as Peyer’s
Platelet P-selectin can facilitate lymphocyte entry into tissues patch and the appendix, and to flat-walled venules in the lamina
because it can simultaneously bind to PNAd on the endothelium propria. α4-integrin can also pair with a β 1 chain to form α4β 1
and PSGL-1 on lymphocytes. E-selectin upregulation requires dimers, which are utilized by lymphocytes primarily in inflam-
new protein synthesis. It is maximally expressed about 4 hours matory conditions. It binds to vascular cell adhesion molecule-1
after induction of inflammation. E-selectin is needed for slow (VCAM-1) on the endothelium and has been proven central in
rolling of leukocytes. It also has an affinity toward PSGL-1, as mediating lymphocyte trafficking into the brain in multiple
well as a specific glycoform of PSGL-1, cutaneous lymphocyte sclerosis.
antigen (CLA). CLA specifically directs lymphocyte trafficking LFA-1 (CD11a/CD18) is a member of the group of leukocyte
to inflamed skin. In addition to PSGL-1, E-selectin has more integrins that contain a unique α chain (CD11 a, b, c, and d) but
private leukocyte receptors, CD44 and E-selectin ligand-1 (ESL-1) share a common β chain (β 2 /CD18). LFA-1 is present on practi-
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(see Fig. 11.5). Mice deficient in both E- and P-selectins have cally all leukocyte subsets. It interacts with its counterreceptors,
more drastic defects in their rolling and leukocyte migration to intercellular adhesion molecules (ICAM-1 and ICAM-2), on the
sites of inflammation than could have been anticipated from endothelial cell surface (see Fig. 11.5). ICAM-1 is upregulated at
mice deficient in only one of the two selectins. This suggests sites of inflammation, whereas ICAM-2 is constitutively present
that E- and P-selectins have overlapping functions and can on the vascular endothelium. To be functional, LFA-1 must be
compensate for each other. activated. Activation of LFA-1 is thought to be primarily a product
of chemokine signaling. Alternative activation pathways include
Chemokines and Their Receptors triggering through glycosyl-phosphatidylinositol (GPI)–linked
Chemotactic cytokines and their receptors (Chapter 10) are molecules and CD44, as well as through other costimulatory
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grouped into four different families based on their primary lymphocyte surface molecules. LFA-1–dependent pathways
protein structure. The families are defined by a cysteine signature display no significant organ specificity in their function.
motif—CXC, CC, C, and CX3C—where C is a cysteine, and X Mac-1 (CD11b/CD18) is also involved in leukocyte migration,
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any amino acid residue. Most chemokines are small, soluble although its contribution is overshadowed by LFA-1. Like LFA-1,
heparin-binding chemoattractants. The relevant chemokines for Mac-1 uses ICAM-1 and ICAM-2 as its ligands (see Fig. 11.5).
leukocyte extravasation are presented to bloodborne lymphocytes Both VCAM-1 and ICAM-1 also play an important role in initiat-
by proteoglycan molecules present on endothelial cell surfaces. ing transmigration, as they mediate the signals to endothelial
During the adhesion cascade, they activate integrins by signaling cells that are needed to change their shape and other properties
via serpentine receptors, which are pertussis toxin sensitive and in order to allow leukocyte entrance. 20
G-protein linked. 19
Different leukocyte subsets bear their own distinct sets of Other Homing-Associated Molecules
receptors, which enable them to respond to chemokines presented Several other molecules belonging to various molecular families
on the vascular endothelium as well as within tissues. For example, also participate in the adhesion cascade. CD44 is a multifunctional
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CCL21 and CCL19 are preferentially expressed by HEVs that proteoglycan found on a large variety of different cell types.
are found in the interfollicular areas within a lymph node. They Using endothelial hyaluronan as its ligand, it mediates lymphocyte
preferentially attract T cells bearing the CCR7 receptor and thus rolling. It can form bimolecular complexes with α 4β 1 that
draw T lymphocytes from blood and into these areas. Fractalkine, strengthen leukocyte–endothelial cell interaction. In vivo inhibi-
a CX3C chemokine, can be produced in either a soluble or a tion studies using function-blocking antibodies indicate that
membrane-anchored form. It can be found on the HEVs in CD44 plays an important role in directing lymphocyte trafficking
peripheral lymph nodes and has potent chemoattractant activity to sites of inflammation (e.g., skin and joints).
for T cells. The major attractants for B cells are CXCL12 and CD31, a member of the immunoglobulin superfamily, is found
CXCL13. on many subsets of lymphocytes as well as in the continuous
Although many chemokines are present in different organs in endothelium of all vessel types. It is expressed primarily at the
the body, some selectivity in their expression can guide tissue- intercellular junctions and is involved in a stimulus-specific
selective leukocyte trafficking. For example, CCL25 attracts manner in transmigration, especially through the endothelial
CCR9-positive lymphocytes to the small intestine, and CCL17 basement membrane. Other molecules involved in the transmigra-
and CCL22 attract CCR4-bearing lymphocytes to the skin. Che- tion process are CD99 and junctional adhesion molecules A and
mokines can form heteromeric complexes to activate chemokine C, which are expressed on both leukocytes and endothelial cells.
receptors. For example, CXCL13 can enhance triggering of CCR7 These molecules interact sequentially in a homotypic fashion
by CCL19 and CCL21. Conversely, formation of chemokine during diapedesis. Endothelial JAM-A can also use LFA-1, JAM-C
complexes may protect a chemokine from degradation. 18 can utilize Mac-1, and JAM-B can use α 4 β 1 as leukocyte ligands.
The role of ecto-enzymes in the adhesion cascade has been
Integrins and Their Immunoglobulin Superfamily Ligands recently recognized. 22,23 Vascular adhesion protein-1 (VAP-1),
Integrins are a large family of heterodimeric molecules consisting CD73, and CD38 have well-established roles in leukocyte traf-
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of an α and a β chain. Traditionally, they are thought to mediate ficking. Because of their enzymatic properties, they can rapidly