Th1 versus Th2 Chemokine Receptor Profiles

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Although there are exceptions to the rule (1), differential chemokine receptor expression tends to be present under Th1 and Th2 inflammatory conditions. Under Th1 conditions, CXCR3 and, to a lesser extent, CCR5 predominate. Conversely, under Th2 conditions, CCR3, CCR4, and CCR8 are preferentially expressed. Thus, under Th1-promoting conditions, CXCR3 ligands including 10 kDa interferon-gamma-induced protein (IP-10)/CXCL9, gamma interferon-induced monokine (MIG)/CXCL10, and interferon-inducible T-cell alpha che-moattractant (I-TAC)/CXCL11 preferentially attract Th1 T cells. CCR3, CCR4, and CCR8 ligands, including eotaxins/CCL 11, 24, 26, monocyte-derived chemokine (MDC)/CCL22, thymus associated regulatory chemokine (TARC)/ CCL17, and T-cell activation protein 3 (TCA-3)/CCL1, preferentially attract Th2 cells, eosinophils, mast cells, and basophils.

Clinical evidence tends to support the Th1/Th2 differential chemokine receptor paradigm, represented primarily as CXCR3 versus CCR4. Pulmonary CCR4+CD4+ cells and levels of CCL17 and CCL22 were significantly increased in asthmatic children versus children with nonasthmatic chronic cough or without airway disease. In asthmatic children, CCR4+CD4+ cells correlated positively with levels of CCL17, CCL22, serum IgE levels, and negatively with FEV 1 (forced expiratory volume in the first second of exhalation, a measure of lung function). Conversely, CXCR3+CD8+ cells and levels of CXCL11 were significantly increased in children with nonatopic chronic cough compared with the other groups (2). These results have been recapitulated in segmental allergen challenge studies. In asthmatics, a majority of T cells in post-allergen challenge biopsies expressed CCR4 (3,4). Expression of the CCR4 ligands CCL22 and CCL17 was also upregulated on airway epithelial cells upon allergen challenge (3). CCR4 expression was not found on T cells from patients with chronic obstructive pulmonary disease, which instead expressed CXCR3 (4). Cumulatively, these results demonstrate an increase in CCR4-expressing T cells in allergic airways and increased production of CCL17 and CCL22. Furthermore, these results demonstrate that the increase in CCR4 expression by T cells in allergic lungs may serve to differentiate allergic from nonallergic inflammation.

One potential mechanism for the continued polarization of T-cell chemokine receptor expression during inflammatory lung disease is that chemokines can also serve as receptor antagonists. CXCR3 ligands act as antagonists of CCR3, and CCL11 can serve as an antagonist for CXCR3 (5,6). Thus, Th1-type

Expression of Chemokine Receptors by Leukocytes and Structural Cells in Allergic Lung Disease

CCR1

CCR2

CCR3

CCR4

CCR6

CCR8

CXCR1

CXCR2

CXCR3

CXCR4

T cells, B cells

++

++

++

++

++

++

++

++

Eosinophils/basophils

++

+

++

++

++

++

Neutrophils

+

+

+

+

+

+

Mast cells

++

++

++

++

+

+

+

+

Epithelial cells

++

+

+

+

Airway smooth muscle cells

+

++

++

Monocyte/macrophages

+

++

++

+

Fibroblasts

+

+

+

Dendritic cells

+

+

+

++

+

+

+

+

+

Note: +, expressed by cell type; ++, evidence for role in allergic lung disease.

Note: +, expressed by cell type; ++, evidence for role in allergic lung disease.

chemokines may simultaneously promote Th1 and antagonize Th2, similar to Th1 and Th2 cytokines.

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