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CHaPTEr 10 Chemokines and Chemokine Receptors 163

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N-formyl peptides), cell adhesion, antigen uptake, T-cell costimu- transition to the CD4 or CD8 single-positive stage (Fig. 10.4).
lation, and diverse transcription factors (e.g., NF-κB). In innate Just before thymic egress, thymocytes become CCR9 negative
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immunity, proinflammatory cytokines, such as interleukin-1 and upregulate L-selectin. Transition from CD4 CD8 thymocytes
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(IL-1), tumor necrosis factor (TNF), and IL-15 induce expression in the cortex to CD4 or CD8 single-positive thymocytes in the
of inflammatory chemokines important for recruitment of medulla is associated with upregulation of CCR4 and CCR7,
myeloid and NK cells. In adaptive immunity, signature cytokines receptors for CCL22, and CCL19 and CCL21, respectively, which
of polarized helper T cells establish positive feedback loops are expressed in the medullary stroma. Accordingly, these che-
for production of signature chemokines able to specifically mokines attract thymocytes between the late cortical and medul-
recruit these cells. For example, T helper-1 (Th1) cells produce lary stages of development in vitro. Neutralization studies suggest
interferon-γ (IFN-γ), which induces expression of CXCL9, that egress of newly formed T cells from the fetal thymus to the
CXCL10, and CXCL11, the chemokine agonists specific for the circulation is mediated by CCL19, which is selectively localized
signature Th1 cell chemokine receptor CXCR3. This amplifies on endothelial cells of medullary venules and acts at CCR7 on
Th1 cell recruitment. Similar loops may exist for Th2 cells mature thymocytes.
involving CCL17/CCR4 and IL-4, as well as for Th17 cells involv-
ing CCL20/CCR6 and IL-17. IFNs, glucocorticoids, and antiin- Tissue
flammatory cytokines (e.g., IL-10 and transforming growth Once myeloid cells are released from bone marrow, they undergo
factor-β [TGF-β]) can inhibit inflammatory chemokine gene specific trafficking itineraries and in some cases become resident
expression. Chemokines can also be regulated at the level of in tissue. This is regulated, in part, by specific chemokines. For
messenger ribonucleic acid (mRNA) stability. example, CXCL14 is important for macrophage positioning in
A chemokine gene can generate families of proteins varying in the lung, and CCL11 and its receptor CCR3 for eosinophils in
activity and potency by alternative splicing and posttranslational the spleen and the gastrointestinal tract. CCR6 regulates position-
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modification, especially N- and C-terminal proteolytic trimming. ing of immature myeloid CD11c CD11b DCs in the subepithelial
Proteases can target many chemokines (e.g., CD26 [dipeptidyl dome of Peyer patches. CX3CR1 regulates localization of myeloid
peptidase IV] and matrix metalloproteinases [MMPs]), or DCs in Peyer patches and may be important for antigen sampling
few or only one (e.g., TACE [the TNF-α–converting enzyme], from the intestine.
plasmin, urokinase plasminogen activator, and cathepsin G).
Chemokine action can be blocked by atypical chemokine recep- CHEMOKINE REGULATION OF THE
tors (e.g., ACKR1), endogenous receptor antagonists, receptor IMMUNE RESPONSE
decoys, and autoantibodies. Cytokines may also convert a
signaling receptor into a decoy (e.g., IL-10 inactivates CCR2 on The innate and adaptive immune systems are deployed separately
monocytes). but are assembled, in part, by specific sets of chemokines and
chemokine receptors (see Fig. 10.4). 15
CHEMOKINE REGULATION OF HEMATOPOIESIS Innate Immunity

Bone Marrow Platelet-Derived Chemokines
Most chemokines that modulate hematopoietic progenitor cell Made primarily during platelet development, stored in platelet
(HPC) proliferation ex vivo act early during hematopoiesis and α granules, and rapidly released during platelet degranulation,
are inhibitory. CXCL12, the most abundant chemokine in bone CXCL4 and CXCL7 are among the first chemokines to appear
marrow, is an important exception. CXCL12 signaling through at sites of tissue injury and infection. When there is hemorrhage
its receptor CXCR4 is critical for bone marrow myelopoiesis and and vascular damage, chemokine concentrations can reach
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B-cell lymphopoiesis. CXCR2 and CXCR4 both regulate neutrophil elevated levels. CXCL7 can function as an immediate-early
egress from bone marrow, and CXCR4 is also critical for mobiliza- mediator of neutrophil recruitment released from platelets at
tion of hematopoietic stem cells (HSCs) and HPCs from bone sites of inflammation. Although it is not a prominent leukocyte
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marrow. A second CXCL12 receptor, ACKR3 (previously known chemoattractant and does not induce degranulation of neutrophil
as CXCR7), does not regulate hematopoiesis, but interestingly lysosomal enzymes, CXCL4 is able to induce neutrophil secondary
it is an essential factor responsible for cardiac valve development granule exocytosis and release of matrix-degrading enzymes,
apparently due to its ability to bind the nonchemokine ligand which may facilitate neutrophil penetration of infected or injured
adrenomedullin. ACKR3 also regulates marginal zone B-cell tissues.
positioning in the spleen. CCR2 is important for monocyte release
from bone marrow. CXCL8 and CXCR2
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All seven ELR CXC chemokines preferentially recruit neutrophils
Thymus in vitro by binding to CXCR2. Two of these, CXCL6 and CXCL8,
During development, T cells must migrate from the thymic cortex are also potent agonists at CXCR1, which is coexpressed at
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to the medulla (Chapter 8). Chemokines and chemokine receptors similar levels on neutrophils. These seven chemokines are
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are differentially expressed in thymus and coordinate migration. rapidly inducible but may differ biologically because of temporal
CCR9 and its ligand, CCL25, may be important, since competitive and spatial differences in expression. These differences provide
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transplantation of CCR9 bone marrow is less efficient than a mechanism for the graded navigation of neutrophils through
normal marrow at repopulating the thymus of lethally irradiated tissue. Blocking studies in multiple animal models have dem-
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Rag-1 mice. onstrated the importance of CXCL8 and CXCR2 in neutrophil
CCL25 is expressed by medullary DCs and both cortical and accumulation in response to infectious and noninfectious
medullary epithelial cells. CCR9 is expressed on the majority of stimuli. Intradermal injection of CXCL8 in humans causes rapid
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immature CD4 CD8 thymocytes but is downregulated during (<30 min) and selective accumulation of large numbers of