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CHaPTEr 11 Lymphocyte Adhesion and Trafficking 173

surrounding the central arteriole in the white pulp, a location
known as the periarteriolar sheath. B cells are scattered in the MOLECULAR MECHANISMS INVOLVED IN
corona that surrounds these T-cell areas. Most splenic lymphocytes LEUKOCYTE EXTRAVASATION FROM BLOOD
leave the spleen via the splenic vein. The mechanisms that control INTO TISSUES
the entry and exit of lymphocytes from the spleen remain
incompletely understood but include chemokines, oxysterols, The Adhesion Cascade
and sphingosine 1 phosphate. Dynamic interactions between leukocytes and endothelial cells
can be observed both in vitro and in vivo. For example, leukocyte
adhesion can be followed in vivo in experimental animals and
KEY CONCEPTS even in human tissues by intravital microscopy (Fig. 11.3).
Adhesion Molecules in Inflammation Leukocyte–endothelial cell interaction during the extravasation
cascade can be divided into a series of phases, or steps, that all
• Adhesion molecules are important in directing leukocyte traffic to leukocyte subtypes, including lymphocytes, are thought to follow
sites of inflammation. (Fig. 11.4). 2,6,11,16
• Numerous inflammatory mediators upregulate and/or induce expression First, the leukocytes marginate out of the main bloodstream
of several endothelial cell adhesion molecules. and begin to tether and roll on the endothelial cell surface.
• Harmful inflammation can be prevented and cured by blocking the This step is mediated primarily by selectins and their mucin-like
function of adhesion molecules.
counterreceptors. This slow-velocity movement culminates in
an activation phase, during which leukocyte chemokine receptors
transmit activation signals by recognizing their chemokine ligands
INFLAMMATION-INDUCED CHANGES presented on the endothelial cell surface. This leads to avidity
IN LEUKOCYTE TRAFFICKING and/or affinity changes in leukocyte integrins, which bind
leukocytes firmly to their immunoglobulin superfamily ligands
During an acute inflammatory response to an antigenic insult, on endothelial cells. Leukocytes then begin to crawl on the
leukocytes can migrate into all nonlymphoid. The inflammation- endothelium. After finding a proper place, they transmigrate
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induced leukocyte migration takes place in characteristic waves. through the endothelium. This transmigration process begins
First, the polymorphonuclear leukocytes rapidly (typically within with interactions between leukocyte integrins, their counter-
1–4 hours) infiltrate into the inflammatory focus. They are receptors, and other molecules. This step is followed by complex
then followed by mononuclear cells (monocytes and lymphocytes). signaling events that lead to protein phosphorylation and dynamic
In a primary challenge, it may take 3 days or more before clustering of the cytoskeleton.
antigen-specific immunoblasts are seen at the peripheral site Leukocytes transmigrate between endothelial cells at the
of inflammation. However, a secondary response by memory endothelial cell junction, which opens transiently and subsequently
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lymphocytes typically has a much shorter lag period. Different closes by localized stimuli. This process requires proteinases,
CD4 T-helper subpopulations, including Th1, Th2, Th17, and such as matrix metalloproteinase-2 (MMP-2), which is induced
regulatory T cells (Tregs; Chapters 8, 16, and 18), CD8 T-cytotoxic in T cells upon adhesion to endothelial cells, as well as other
cells (Chapter 17), and B cells (Chapter 7) can all enter the repair mechanisms that are currently not well known. This
inflamed tissue by using basically the same mechanisms. However, subsequently closes the path of transmigration. Interestingly,
the ratio of these populations and the individual molecules leukocytes can also migrate through endothelial cells in a
employed can vary. 6,12 Successful resolution of an inflam- subtype-specific fashion. For example, polymorphonuclear
matory reaction is also dependent on a coordinated program leukocytes prefer entering via the interendothelial junctions,
involving specialized proresolving lipid mediators (lipoxins, whereas nonactivated lymphocytes may choose the transcellular
resolvins, protectins, and maresins), proteins (annexin A1), route. 11,16
purines (adenosine), and gaseous mediators (e.g., hydrogen
sulfide), all of which serve to halt the inflammatory cell recruit- KEY CONCEPTS
ment and to initiate multiple antiinflammatory, tissue-repairing
mechanisms. 13 Leukocyte–Endothelial Cell Interactions
The normal vascular endothelium in nonlymphoid tissues • Leukocytes interact with the vessel wall in a multistep fashion, using
has a flat, inactive morphology. With inflammation, a series of several leukocyte surface molecules that recognize their counterrecep­
events renders postcapillary venules in these tissues capable of tors on endothelial cells.
binding lymphocytes. The most important changes result from • Selectins mediate the rolling and tethering of leukocytes on the vessel
the proadhesive effects of a multitude of proinflammatory wall.
cytokines that are released by a variety of cell types after being • Chemokines and their receptors activate leukocyte integrins.
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subjected to inflammatory stimuli. If inflammation becomes • Only activated integrins are able to mediate firm adhesion between
leukocytes and endothelium.
chronic, marked histological manifestations become apparent • The transmigration of leukocytes into the tissues requires proteinases
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in the affected nonlymphoid tissues. Most notably, the venules and repair mechanisms.
in these chronically inflamed tissues acquire many of the char-
acteristics of HEVs. Immigrating lymphocytes can form lymphoid
follicles that resemble those seen in lymph nodes. These alterations Certain endothelial molecules involved in the adhesion cascade
have consequences for lymphocyte recirculation pathways. For show organ-specific expression patterns. Analogously, leukocyte-
example, inflamed skin displays characteristics of lymphocyte associated homing molecules display subtype-specific expression
homing that are clearly distinct from those of either mucosal or profiles. Only those leukocytes that have the proper set of
peripheral lymph node systems. 8,15 molecules on their surface can enter a particular tissue because