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142 Part II Cellular Basis of Hematology

of CXCL13, which attracts B cells to B-cell follicles (see later), by respectively). 240,241 As with follicular B cells in LN, antigen encounter
lymphoid stromal cells is strongly dependent on the cytokine lympho- of MZ B cells causes their rapid repositioning to the B-T boundary
toxin (LT)–α1β2 heterotrimer signaling via the LT β receptor. 230–232 area. The retention of naive B cells in the MZ and their relocalization
Correspondingly, mice deficient in LT have no morphologically to the B-T boundary area upon antigen encounter is thought to
233
detectable LNs or PPs. Moreover, CCL21 and CXCL13 have been involve signaling though the phospholipid sphingosine-1 phosphate
shown to be transiently downregulated by a mechanism controlled (S1P) and its receptor S1P 1. 242
by the cytokine interferon-γ. This modulation alters the localiza-
tion of lymphocytes and DCs within responding lymphoid tissues.
As a consequence, priming of T-cell responses to a second distinct LEUKOCYTE EXIT FROM TISSUES
pathogen after chemokine modulation became impaired. Therefore,
transient chemokine modulation may help orchestrate local cellular- Although the coordinated role of adhesion molecules and chemokines
ity, thus minimizing competition for space and resources in activated governing lymphocyte entry into tissues has been examined in great
lymphoid tissues. 234,235 detail, less is known about the exit of these cells from tissues. The
The differential ability of T-cell subsets to migrate in response to final sections of this chapter will discuss examples of emerging
interstitial chemokine gradients is also an important determinant of research on the diverse mechanisms that regulate exit of distinct
236
immunologic memory. For example, LNs harbor not only naive T leukocyte subsets from tissues.
cells, but also a major subset of antigen-experienced cells, the central
memory T cells (T CM ). In steady-state LNs, both T-cell subsets local-
ize in the deep T-cell area and interact dynamically with antigen- Reprogramming Dendritic Cells to Exit Tissues Toward
presenting DCs. However, upon entry of a lymph-borne virus into Secondary Lymphoid Organs
an LN, virus-specific T CM relocalize rapidly toward the outermost LN
regions where virally infected cells are concentrated. This rapid Lymphocyte homing remains without consequence unless lympho-
peripheralization of T CM is coordinated by a cascade of cytokines and cytes encounter DCs that present their cognate antigen. DCs capture
chemokines, particularly ligands for CXCR3 that diffuse from the and present antigen to T cells more efficiently than any other antigen-
outer cortex toward the T-cell area. Antiviral T CM express high levels presenting cell. In general, two routes of antigen delivery to LNs have
of CXCR3 and are responsive to the virus-induced chemokine gradi- been described to date. (1) Antigenic material becomes lymph borne
ent. By contrast, naive T cells do not express CXCR3 and remain and is taken up by DCs that reside in the LN a priori; (2) antigen is
initially sequestered in the T-cell zone. This delayed T-cell response acquired by DCs that reside in peripheral tissues and then transport
in nonimmune hosts allows more time for the viral infection to spread the material to the draining LN. DCs constitutively patrol all tissues
than in immune individuals. Thus, early antigen detection afforded and engulf microorganisms, dead cells, and cellular debris. In the
by intranodal chemokine guidance of T CM is essential for efficient absence of inflammatory stimuli, the cells remain in an immature
antiviral memory. 236 state that is only weakly immunogenic and often stimulates T-cell
tolerance, rather than activation. However, multiple signals associated
Positioning of B Cells Within Secondary Lymphoid with infection or tissue damage can induce DC maturation. Imma-
ture DCs express a variety of chemokine receptors, including as
Organs CCR1, CCR5, and CCR6, which are believed to result in the con-
stitutive homing of immature DCs into tissues, particularly sites of
Similar to T cells, B cells enter secondary lymphoid organs from the inflammation where ligands for these receptors are abundant. 4,115,243–245
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blood to search for their specific antigens. As previously outlined, After exposure to a maturation stimulus, such as Toll-like receptor
the homing and entry of B cells into secondary lymphoid organs such agonists (e.g., lipopolysaccharide, bacterial lipoproteins, peptidogly-
as the LNs and PPs depends on chemokine/receptor interactions that cans or CpG dinucleotides), which often originate from infectious
finally result in firm integrin-mediated adhesion on the surface of pathogens, 246,247 DCs lose CCR1, CCR5, and CCR6, while expres-
HEVs. This adhesion is followed by cell movement into lymphoid sion of GPCRs for lymphoid chemokines, in particular CCR7 and
248
tissue. 140,234,238,239 After entering secondary lymphoid organs, the naive CXCR4, are upregulated. Lymphatic endothelial cells in peripheral
249
B cells travel to B cell–rich areas, the B-cell follicles. This migration tissues express CCL21, the ligand for CCR7. The loss of chemo-
depends on the presence of CXCR5 on the surfaces of B cells and kine receptors that keep the DCs within the tissue together with the
the localized expression of CXCL13 by follicular stromal cells. 109,232,239 increased expression of CCR7 results in the exit of the mature DCs
Follicular B cells are also highly motile, migrating on a network of via the lymphatic drainage system. 138,250 Recently, using a microfluidic
follicular DCs (FDCs), a process that is thought to be necessary to device that allows rapid establishment of stable gradients in three-
ensure optimal surveillance of the FDC for surface-displayed antigen. dimensional matrices, it was shown that CCL21 is a more potent
251
After a period of random migration within follicles, those B cells that directional cue for DC migration than CCL19. DC migration into
have not encountered a cognate antigen return to the circulation via the draining lymphatics also requires β2 integrin binding to ICAM-1
the lymph or, in case of the spleen, via the blood. In contrast, B cells expressed by lymphatic endothelial cells. Moreover, JAM-A, which is
that become stimulated by antigen relocate to the B–T boundary area expressed by DCs and the lymphatic endothelium, also affects DC
to receive help from T cells, which is necessary for further differentia- migration to lymph nodes, because the absence of JAM-A expression
tion. To achieve this repositioning, activated B cells rapidly upregulate by DCs facilitates their migration to lymph nodes. 117,252 The expres-
CCR7. This permits their chemotaxis toward CCR7 ligands expressed sion and activation of β1-integrins, which mediate the interaction of
215
in the T cell–rich zones of the secondary lymphoid organs. Real- DCs with extracellular matrix components, might favor retention of
time imaging revealed that antigen-stimulated follicular B cells ini- DCs in the periphery. 117
tially reduce their migration velocity upon antigen exposure. About While traveling to the draining LN, DCs upregulate the expres-
6 hours later the activated B cells move toward the follicle border sion of molecules for efficient antigen presentation and T-cell stimula-
with the T cell–rich zone and undergo highly dynamic interactions tion, and begin to generate chemokines and other cytokines that
with helper T cells during the following several days. 215 allow them to attract and stimulate T cells. 250,253,254
In the spleen, a subpopulation of “innate” B cells is present in the
marginal zone (MZ) immediately adjacent to the marginal sinus that
surrounds the white pulp cords. The exact extent to which chemokine- Egress of Lymphocytes From Secondary
induced attraction and adhesion affect the positioning of MZ B cells Lymphoid Organs
is still unclear. However, recent studies indicate that the localization
of B cells in the MZ is dependent upon interactions of αLβ2 and When naive lymphocytes do not encounter antigen on antigen-
α4β1 on MZ B cells with their ligands (ICAM-1 and VCAM-1, presenting DCs after a period of random walk, they exit secondary