Cutting Edge: C-C Chemokine Receptor 6 Is Essential for Arrest of a Subset of Memory T Cells on Activated Dermal Microvascular Endothelial Cells Under Physiologic Flow Conditions In Vitro

109

Skin homing T cells carry memory for cutaneous Ags and play an important sentinel and effector role in host defense against pathogens that enter via the skin. CCR10 is a chemokine receptor that is preferentially expressed among blood leukocytes by a subset of memory CD4 and CD8 T cells that coexpress the skin-homing receptor cutaneous lymphocyte Ag (CLA), but not the gut-homing receptor α4β7. Homing and chemokine receptor coexpression studies detailed in this study suggest that the CLA+/CCR10+ memory CD4 T cell population contains members that have access to both secondary lymphoid organ and skin compartments; and therefore, can act as both “central” and “effector” memory T cells. Consistent with this effector phenotype, CLA+/CCR10+ memory CD4 T cells from normal donors secrete TNF and IFN-γ but minimal IL-4 and IL-10 following in vitro stimulation. Interactions of CCR10 and its skin-associated ligand CC ligand 27 may play an important role in facilitating memory T cell entry into cutaneous sites during times of inflammation.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immune Surveillance and Effector Functions of CCR10+ Skin Homing T Cells

Hudak¹,

Hagen²,

Liu³

et al. 2002

109

“…In contrast, 57% of CD4 ϩ CD25 med nonregulatory T cells expressed CCR4, and only 37% expressed CLA, and 38% expressed CCR6. In addition to CLA and CCR4, an important role of CCR6 on skin-homing memory T cells has also been described (21,22). In contrast, relatively few peripheral blood CD4 ϩ CD25 high Treg expressed ␣ 4 ␤ 7 integrin, one of the receptors that would permit them access to lamina propria in the gut.…”

Section: The Majority Of Cd4 ϩ Cd25 High Foxp3 ϩ Treg Express Skin-homentioning

confidence: 99%

The Majority of Human Peripheral Blood CD4+CD25highFoxp3+ Regulatory T Cells Bear Functional Skin-Homing Receptors

Hirahara

Liu

Clark

et al. 2006

249

219

CD4+CD25+ T regulatory cells (Treg) are thought to be important in the peripheral tolerance. Recent evidence suggests that human peripheral blood CD4+CD25+ T cells are heterogeneous and contain both CD4+CD25high T cells with potent regulatory activity and many more CD4+CD25low/med nonregulatory T cells. In this study, we found that virtually all peripheral blood CD4+CD25highFoxp3+ Treg expressed high levels of the chemokine receptor CCR4. In addition, 80% of Treg expressed cutaneous lymphocyte Ag (CLA) and 73% expressed CCR6. These molecules were functional, as CLA+ Treg showed CD62E ligand activity and demonstrable chemotactic responses to the CCR4 ligands CCL22 and CCL17 and to the CCR6 ligand CCL20. The phenotype and chemotactic response of these Treg were significantly different from those of CD4+CD25med nonregulatory T cells. We further demonstrated that blood CLA+ Treg inhibited CD4+CD25− T cell proliferation induced by anti-CD3. Based on homing receptor profile, CLA+ Treg should enter normal skin. We next isolated CD4+CD25high T cells directly from normal human skin; these cells suppressed proliferation of skin CD4+CD25− T cells. Therefore, the majority of true circulating Treg express functional skin-homing receptors, and human Treg may regulate local immune responses in normal human skin.

“…E-selectin/human IgG (100 l at 1 g/ml) and an anti-human ICAM-1 mAb (p79, 1 g/ml) were applied overnight to nontreated plastic culture dishes in TBS as described (10). After a brief rinse with TBS, chemokines (40 l, 10 g/ml) in TBS were applied for 1.5 h at room temperature.…”

Section: In Vitro Flow Assaysmentioning

confidence: 99%

“…CCL20, a ligand for CCR6, is strongly up-regulated in both HUVEC and human dermal microvascular endothelial cells (HDMEC) by inflammatory cytokines such as TNF-␣ (10,18). Our previous study showed that inhibition of CCR6 effectively prevented the arrest of mTC on TNF-␣ activated HDMEC under shear stress, suggesting that CCR6 was required for efficient arrest of a arrest of a subset of mTC on acutely inflamed vascular endothelium (10).…”

mentioning

confidence: 99%

CCR6 Colocalizes with CD18 and Enhances Adhesion to Activated Endothelial Cells in CCR6-Transduced Jurkat T Cells

Maki¹,

Morales²,

Carroll³

et al. 2002

Self Cite

CCR6 is expressed by memory T cells (mTC) and is a requirement for efficient arrest of a subset of mTC to activated human dermal microvascular endothelial cells (HDMEC) under physiologic shear stress. We now address whether CCR6 alone is sufficient to induce arrest of a model T cell line (Jurkat) that shows low expression of all CCRs tested (CCR1–10). Herein, we transduced Jurkat (JK) T cells expressing fucosyltransferase VII with a chimeric chemokine receptor consisting of CCR6 fused to enhanced green fluorescent protein. In contrast to the starting JK lines, the resulting cell line (JK fucosyltransferase VII-CCR6) migrated 6-fold better to CCL20 in chemotaxis assays, arrested in response to CCL20 that was immobilized to plastic, and demonstrated a 2.5-fold increase in adhesion to activated HDMEC (p = 0.001). Adhesion was blocked by anti-CD18 mAb (p = 0.005) but not by anti-CD49d mAb (p = 0.3). After arrest on recombinant substrates, CCR6 clustered on the surface as detected by real-time observation of enhanced green fluorescent protein fluorescence. Dual-label confocal microscopy revealed that LFA-1 (CD18 and CD11a), but not CXCR4, colocalized with clustered CCR6 in the presence of immobilized CCL20. Thus, the functional expression of CCR6 is sufficient to provide the chemokine signaling necessary to induce arrest of a JK T cell line to activated HDMEC. Clustering of CCR6 and coassociation with critical integrins may serve to strengthen adhesion between T cells and activated endothelial cells.