Page 183 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 13 Chemokines and Hematopoietic Cell Trafficking 141

hematopoietic precursors are also present in peripheral blood. 10–13 whereas administration of a beta(2) adrenergic agonist enhanced
Blood-borne HSCs continuously migrate back to the BM cavity, HSPC mobilization. Therefore, the sympathetic nervous system regu-
13
presumably to fill any vacant stem cell niches. Although the exact lates the attraction of stem cells to their niche via transduction of
physiologic relevance of blood-borne HSCs remains to be determined, circadian information from the central pacemaker in the brain, the
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the intrinsic capacity of HSCs to home to the BM compartment is suprachiasmatic nucleus, to the BM microenvironment. Recent
the prerequisite for successful clinical BM and stem cell transplanta- data show that circadian regulation is regulated by beta-2 and beta-3
tion. Homing of HSCs to the BM is a rapid process, as intravenously adrenergic receptors (beta-ARs) expressed on HSCs, osteoblasts, and
injected murine and human progenitors are quickly cleared from the mesenchymal stem/progenitor cells. Moreover, beta(2)-ARs and
recipient’s circulation. 13,175,176 Like mature lymphocytes, HSCs and beta(3)-ARs have specific roles in stromal cells and cooperate during
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hematopoietic progenitor cells (HPCs) interact through a multistep progenitor mobilization. Whereas activation of beta(3)-ARs down-
adhesion cascade with BM microvessels. 7,176–180 Initially, HPCs tether regulates Cxcl12, beta(2)-AR stimulation induces clock gene expres-
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and roll along BM microvessels. 181,182 This process involves α4β7 sion. In addition, double deficiency in beta(2)-ARs and beta(3)-ARs
integrin on HSCs/HPCs, which binds VCAM-1, as well as E- and compromises enforced mobilization. Therefore, these data demon-
P-selectin on BM sinusoidal endothelial cells, which bind α(1–3)- strate that HSC trafficking and hematopoiesis do not escape the
fucosylated ligands including CD44 and PSGL-1 on the surface of circadian regulation that controls most physiologic processes. For the
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HPCs. The subsequent firm arrest is mediated by activated α4β1 clinical settings, the timing of stem cell harvest or infusion may
and VCAM-1, which is constitutively expressed in BM sinusoids. In influence the yield or engraftment, respectively, and may result in
addition to α4β1 integrin, the integrins α4β7, α5β1 and α6β1, and better therapeutic outcomes. 210
CD44 as well as JAM-B have recently been implicated in HSC
homing to the BM. 180,183–186 Integrin-mediated adhesion is important
for HSPC movement not only in adulthood but also during embryo- LEUKOCYTE MIGRATION WITHIN TISSUES
genesis. Thus, HSPCs in the yolk sac, aorto-gonad-mesonephros
region, and placenta express CD41 (GPIIb integrin encoded by the Trafficking Patterns of Lymphocytes
gene Itga2b). Expression gradually decreases during development,
and adult HSPCs express little or no CD41. 7,187 In addition to CD41, After a leukocyte has accessed a tissue, it must migrate to specific
β1 integrins tune the migration of fetal HSPCs. The use of chimeric interstitial positions. As discussed earlier, homing typically requires
mice generated with β1 integrin-deficient fetal HSPCs has revealed that the blood-borne leukocyte completes a complex tissue- and
that fetal HSPCs lacking β1 integrins form and differentiate but they subset-specific multistep adhesion cascade. One exception to this rule
cannot colonize the follicular lymphoma, suggesting an essential role is the spleen, where most blood-borne lymphocytes can leave the
of β1 integrins in fetal HSPC trafficking. The role of the β2-integrins circulation even in the absence of multiple traffic molecules. However,
LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) is controversially chemokines are essential in all lymphoid organs, including the spleen,
discussed. Although some studies have reported their involvement in to guide the newly arrived lymphocytes to their proper position
HSPC retention, 188,189 others have indicated that the effect of β2 within the organ.
integrins becomes apparent only in synergy with α4β1. 190 Multiphoton intravital microscopy was used as a tool to decipher
The chemokine CXCL12, the ligand for CXCR4 expressed by the mechanisms that control the extravascular traffic patterns of
most hematopoietic cells including HSCs, is thought to play a pivotal homed lymphocytes within lymphoid and nonlymphoid tissues. 212–220
role in BM homing of HSCs. BM endothelial cells (in addition to For example, imaging experiments have shown that T cells that have
immature osteoblasts and other stromal cells) constitutively express entered an LN move incessantly within the paracortex (T-cell area).
and secrete CXCL12. 177,191–194 However, alternate pathways appear Here, they query the resident DCs for the presence of antigens that
to exist because fetal liver-derived mouse HSCs home to the BM activate their T-cell receptor. B cells that home to LNs migrate to the
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of adult recipients independent of CXCR4, and adult HSCs more superficial B-cell–rich follicles, where they may detect antigens
treated with a CXCR4 antagonist are still able to home sufficiently presented by follicular DCs. Activated B cells that encounter antigens
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to the BM. This indicates that HSCs may use different recep- then move to the margins of the B- and T-cell zones. Here, they
tors and/or respond to distinct integrin-activation signals. In this can receive help from antigen-specific CD4 T cells. Analogous specific
context, the recent description of CXCR7, an alternate receptor microenvironments for T and B cells also exist in the other lymphoid
for CXCL12, may explain some of the seemingly contradictory tissues.
findings. 197
Of note, the CXCL12/CXCR4 axis is not only involved in the
homing process of HSCs to the BM, but (among others) has also Migration of T Cells to T Zones Within Secondary
been linked to the retention of HSCs within stem cell niches and to Lymphoid Organs
the regulation of the maturation of more committed HPCs (in par-
ticular, B-cell progenitor cells). 59,198–202 Correspondingly, disruption After homing to secondary lymphoid organs, T cells migrate within
of the CXCL12/CXCR4 pathway leads to premature release of HPCs the T zones. They engage in highly motile amoeboid movement
into the peripheral blood. 203,204 HPCs lacking CXCR4 accumulate in (average speed ~12 µm/min) and undergo multiple brief encounters
the circulation and fail to undergo normal lymphopoiesis and myelo- with resident DCs. 221–223 In this context, the fibroblastic reticular cell
poiesis, most likely because the cells do not receive the required (FRC) network regulates naive T-cell access to the paracortex and also
maturation signals. Interestingly, upregulation of metalloproteinases supports and defines the limits of T-cell movement within this
(see earlier), which cleave and inactivate CXCR4 and CXCL12, has domain. 224,225 As a consequence of high T-cell motility, it has been
recently been implicated in HSC mobilization. 205–208 Mechanisms estimated that every DC in an LN touches as many as 5000 naive T
that modulate the CXCR4/CXCL12 axis are also thought to play a cells within 1 hour. When T cells encounter a specific antigen, they
role in the coordinated mobilization of HPCs in response to cytokines progressively decrease their motility, become activated, and form
that are used for this purpose in clinical practice. 58 long-lasting stable conjugates with DCs. Finally, antigen-experienced
In addition to CXCL12, the egress from BM niches has been T cells start to proliferate and resume their rapid migration while
recently shown to be critically dependent on the nervous system. contacting DCs only briefly. 223,226
Thus, it was found that the mouse line exhibiting aberrant nerve The positioning and high motility of T cells in the T-cell
conduction (UDP-galactose ceramide galactosyltransferase-deficient area is dependent on CCR7 and its ligands CCL19 and
−/−
[Cgt ] mice) was characterized by the absence of HSPC egress from CCL21. 110,138,139,212,227,228 Both ligands are abundantly expressed in
BM following granulocyte colony-stimulating factor (G-CSF) or T zones by radiation-resistant stromal cells. Notably, ectopic expres-
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fucoidan administration. Interestingly, norepinephrine signaling– sion of CCL21 induces the formation of LN-like structures in the
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controlled bone CXCL12 downregulation and HSPC mobilization, pancreas of mice. The expression of CCL19 and CCL21, but also