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140 Part II Cellular Basis of Hematology

(which are immunologically distinct from PNAd) expressed by HEVs a crucial mechanism for the fine-tuning of the migratory cellular
in PPs are considerably lower when compared with LNs. 143,144 As a responses. 65,156,157
result, L-selectin itself is not sufficient to initiate a successful homing In contrast, the migratory properties acquired by T and B lym-
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cascade for most lymphocytes in PPs. Indeed, HEVs in PPs (and phocytes in response to activation are diverse depending on the
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also in mucosa-associated LNs) additionally express MAdCAM-1, a strength, the quality, and the context of the antigenic stimulus.
ligand for the α4β7 integrin. 143–145 The α4β7 heterodimer, which Specifically, antigen stimulation of naive lymphocytes results in the
comprises an α4 integrin chain (CD49d) linked to the β7 integrin generation of effector and memory cells that express specific reper-
chain, is expressed at low levels by naive T and B cells, and is required toires of trafficking molecules that guide them back to tissues con-
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for the successful homing of these cells in PP HEVs. Following taining the stimulatory antigen. 158–160 Thus, a cutaneous challenge
formation of an initial L-selectin–dependent tether, the α4β7– generates preferentially a skin-tropic memory response, whereas orally
MAdCAM-1 pathway stabilizes and slows the rolling lymphocytes ingested antigens induce preferentially gut-homing effector and
without requiring chemokine activation. Once a chemokine signal memory cells. Recent studies have broadened our understanding of
has been transmitted, both α4β7 and LFA-1 become activated and the molecular events that induce the generation of tissue-specific
jointly mediate firm arrest. 143 memory cells.
Of note, α4β7 is strongly upregulated on gut-homing effector/ In addition to presenting antigen, DCs in different lymphoid
memory lymphocytes, but completely absent on skin-homing organs are endowed with information characteristic for the tissue in
memory T and B cells; these differential levels of α4β7 integrin which the antigen was obtained. DCs in mucosa-associated lymphoid
expression allow certain antigen-experienced lymphocyte subsets to tissues, but not other lymphoid organs, possess the enzymatic
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acquire tissue selectivity. The mechanisms underlying this specific- machinery to synthesize retinoic acid (RA) from vitamin Ab.
ity and plasticity of lymphocyte homing will be addressed later. Like Exposure of activated T cells to RA induces the expression of gut-
in LNs, chemokines are essentially involved in promoting integrin homing receptors (i.e., α4β7 and CCR9) and suppresses skin-homing
activation and allowing firm lymphocyte arrest in HEVs of PPs. Thus, molecules. 159,162 In the absence of RA, T-cell stimulation induces few
CXCR4, CXCR5, and CCR7 have been implicated in B-cell homing, or no gut-homing molecules, but instead promotes the expression of
while CCR7 seems exclusively responsible for T-cell homing. Interest- P- and E-selectin ligands, as well as CCR4, which are needed for
ingly, while T and B cells are recruited across the same HEVs in LNs, homing to the skin. Additionally, when activated T cells are exposed
there is segmental segregation of T- and B-cell recruitment in PPs. to IL-12 and high levels of vitamin D3, which is physiologically
HEVs supporting B-cell accumulation in PPs are concentrated in or induced by sunlight in the skin, they upregulate CCR10, the receptor
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near B follicles and present CXCL13, but not CCL21, whereas T for the epidermal chemokine CCL27. This organ-specific informa-
cells preferentially accumulate in interfollicular HEVs (i.e., within tion can reprogram and “imprint” the tissue-tropic memory cells as
the T-cell area), which express high levels of CCL21 but not CXCL13. they differentiate from naive lymphocytes. 160
Like T cells, B-cell subsets also express homing receptors that
Trafficking of Leukocytes From Blood Into permit their selective trafficking to specific tissues. For example,
distinct B-cell subsets produce the immunoglobulin isotype IgA,
Nonlymphoid Tissues which is present in secreted body fluids, including tears, breast milk,
+
and mucus. IgA B cells are characterized by their expression of
As outlined previously, naive lymphocytes migrate most efficiently CCR10. 164,165 The ligand for CCR10, MEC/CCL28, is expressed
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into secondary lymphoid organs, from which innate immune cells predominantly in mucosal tissues that secrete IgA. Hence, CCR10
are excluded. However, both innate immune cells and subsets of may function as a homing receptor that allows IgA-secreting B cells
lymphocytes can respond to inflammatory and/or activation signals to migrate to tissues where IgA is required. A large subset among the
by modulating the expression and/or activity of traffic molecules, IgA-secreting B cells are those in the small intestine, which in addi-
4
which allows them to migrate to nonlymphoid tissues. For example, tion to CCR10 express the gut-homing receptors α4β7 and CCR9.
in response to inflammatory stimuli, granulocytes, including neutro- When naive B cells are activated in the presence of intestinal DCs,
phils, eosinophils, and basophils, are rapidly recruited into the they upregulate not only these two traffic receptors, but also undergo
affected site and provide the first line of antimicrobial defense. class switching to IgA. This imprinting effect is dependent upon RA,
Thereafter, additional immune cells, including monocytes, DCs, and which is sufficient to induce gut-homing receptors, but must be
effector as well as memory lymphocytes, may be recruited. Essentially, combined with DC-derived IL-5 or IL-6 to promote IgA class switch-
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all of these different recruitment events depend on distinct multistep ing. More than 50 different subtypes of lymphocytes have been
adhesion cascades. characterized in human blood and it is likely that multiple similar
Many of the inflammation-associated traffic molecules required associations between homing receptors, immunologic effector func-
for access into nonlymphoid tissues are shared by the different leu- tion, and tissue specificity will be revealed in future.
kocyte subsets. The key receptors that initiate capture and mediate
rolling of neutrophils, monocytes, natural killer cells, eosinophils,
and effector T and B cells at peripheral sites of injury and inflam- Migration of Hematopoietic Stem Cells to the Bone
mation are the three selectins, the leukocyte-expressed L-selectin Marrow and Mobilization in the Niche
as well as P- and E-selectin, which are induced on both acutely
and chronically stimulated endothelial cells. 147–151 In addition, The BM is the principal site of hematopoiesis in the adult body.
interactions between leukocytes involving PSGL-1 and L-selectin Correspondingly, most HSCs are lodged in the BM cavity. Within
can also support the accumulation of immune cells in inflamed the BM, maintenance of HSCs and regulation of their self-renewal
tissues. 150,152–154 Subsequent to rolling, firm arrest of leukocytes in and differentiation is thought to depend on the specific microenvi-
nonlymphoid tissues involves integrins, including CD11a/CD18 ronment, which has historically been termed stem cell niche. 6,8,167–169
(and its counter-ligand ICAM-1 and possibly also ICAM-2), VLA-4 The central role of stem cell niches for HSC function has been rec-
d
(and its counter-ligand VCAM-1), as well as CD11b/CD18 (and ognized with the discovery that Sl/Sl (steel-Dickie) mice bearing a
its counter-ligand ICAM-1). 1,27,155 As discussed above for lymphoid mutation in the gene encoding membrane-bound stem cell factor
tissues, chemoattractants, including chemokines and other GPCR (SCF; also known as KIT ligand) show failure of BM HSC mainte-
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agonists, such as formyl peptides, complement fragment 5a, and nance. However, the exact localization as well as the composition
lipid mediators (e.g., PAF and LTB4), contribute essential integrin- of BM HSC niches and the molecular cross-talk that controls the
activation signals for leukocytes at sites of inflammation. The retention of HSC within the niches are the subject of intense ongoing
molecular diversity of chemoattractants and their restricted temporal research. 171–174
and spatial expression patterns combined with leukocyte subset- Notably though, not all HSCs reside within the BM. In fact, it
specific fingerprints of chemoattractant receptor expression provide has been known for almost four decades that a small amount of