CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell-attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin - PubMed (original) (raw)

CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell-attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin

Y Reiss et al. J Exp Med. 2001.

Abstract

The chemokine thymus and activation-regulated chemokine (TARC; CCL17) is displayed by cutaneous (but not intestinal) venules, and is thought to trigger vascular arrest of circulating skin homing memory T cells, which uniformly express the TARC receptor CC chemokine receptor (CCR)4. Cutaneous T cell-attracting chemokine (CTACK; CCL27), expressed by skin keratinocytes, also attracts cutaneous memory T cells, and is hypothesized to assist in lymphocyte recruitment to skin as well. Here we show that chronic cutaneous inflammation induces CD4 T cells expressing E-selectin binding activity (a marker of skin homing memory cells) in draining lymph node, and that these E-selectin ligand+ T cells migrate efficiently to TARC and to CTACK. In 24 h in vivo homing assays, stimulated lymph node T cells from wild-type mice or, surprisingly, from CCR4-deficient donors migrate efficiently to inflamed skin; and an inhibitory anti-CTACK antibody has no effect on wild-type lymphocyte recruitment. However, inhibition with anti-CTACK monoclonal antibody abrogates skin recruitment of CCR4-deficient T cells. We conclude that CTACK and CCR4 can both support homing of T cells to skin, and that either one or the other is required for lymphocyte recruitment in cutaneous delayed type hypersensitivity.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

Generation of E-lig+ CD4 memory T cells after cutaneous immunization with DNFB. T lymphocytes from draining LN and inflamed skin of wild-type (a) and CCR4−/− mice (b) treated with immunogen (DNFB) were isolated and analyzed by flow cytometry for E-lig+ expression in comparison to LN cells from untreated mice. Induction of E-lig+ T cells in LN, and the localization of E-lig+ T cells in inflamed ears, were not significantly altered in CCR4-deficient mice (b). The fraction of CD4 T cells of memory phenotype in skin-draining LNs was also similar (c). T cells are gated on memory T cells (CD4+ CD44highCD45RBlow). Additional controls (E-selectin Ig chimera + EDTA on LN cells) were also negative (not shown). The data are representative of 6 (a and b) and 10 (c) experiments.

Figure 2.

Figure 2.

Migration of E-lig+ CD4 memory T cells to TARC, MDC, and CTACK. T lymphocytes from LN draining a cutaneous DTH site were isolated and migrated to TARC, MDC, CTACK, or SLC in a transwell chemotaxis assay (background migration to medium alone is subtracted). Both, E-lig+ and E-lig− wild-type (a) and CCR4−/− (b) CD4 memory T cells migrate equally well to SLC. Chemotaxis to MDC and TARC correlates with E-lig+ expression and is CCR4 dependent as CCR4−/− cells do not respond (a and b). Similarly, E-lig+ but not E-lig− wild-type and CCR4−/− CD4 memory T cells are attracted by CTACK (c and d). The data are mean ± SEM of three to seven experiments.

Figure 3.

Figure 3.

CCR4 is not essential for T cell homing to inflamed skin in DTH. Adoptively transferred wild-type and CCR4−/− donor T cells (Thy1.2+) home with the same efficiency to the inflamed skin of Thy1.1 recipients (a). Background (false Thy1.2+ cells in recipients with no donor cells, <0.2%) has been subtracted. Data are percentage of donor (Thy1.2+) T cells among CD4 T cells, normalized to LN values (mean ± SEM of seven experiments). Donor Thy1.2+ CD4 cells ranged from 2 to 10% of LN CD4 cells in the different experiments presented here. SPL, spleen. (b) L-selectin staining of wild-type and CCR4−/− donor LN T cells (primarily naive cells; representative results, n = 3). (c) CFSE labeling of donor cells revealed that few LN- or skin-homing T cells had undergone division in the course of our experiments.

Figure 3.

Figure 3.

CCR4 is not essential for T cell homing to inflamed skin in DTH. Adoptively transferred wild-type and CCR4−/− donor T cells (Thy1.2+) home with the same efficiency to the inflamed skin of Thy1.1 recipients (a). Background (false Thy1.2+ cells in recipients with no donor cells, <0.2%) has been subtracted. Data are percentage of donor (Thy1.2+) T cells among CD4 T cells, normalized to LN values (mean ± SEM of seven experiments). Donor Thy1.2+ CD4 cells ranged from 2 to 10% of LN CD4 cells in the different experiments presented here. SPL, spleen. (b) L-selectin staining of wild-type and CCR4−/− donor LN T cells (primarily naive cells; representative results, n = 3). (c) CFSE labeling of donor cells revealed that few LN- or skin-homing T cells had undergone division in the course of our experiments.

Figure 3.

Figure 3.

CCR4 is not essential for T cell homing to inflamed skin in DTH. Adoptively transferred wild-type and CCR4−/− donor T cells (Thy1.2+) home with the same efficiency to the inflamed skin of Thy1.1 recipients (a). Background (false Thy1.2+ cells in recipients with no donor cells, <0.2%) has been subtracted. Data are percentage of donor (Thy1.2+) T cells among CD4 T cells, normalized to LN values (mean ± SEM of seven experiments). Donor Thy1.2+ CD4 cells ranged from 2 to 10% of LN CD4 cells in the different experiments presented here. SPL, spleen. (b) L-selectin staining of wild-type and CCR4−/− donor LN T cells (primarily naive cells; representative results, n = 3). (c) CFSE labeling of donor cells revealed that few LN- or skin-homing T cells had undergone division in the course of our experiments.

Figure 4.

Figure 4.

Anti-CTACK antibody inhibits donor CCR4−/− but not wild-type T cell recruitment to inflamed skin. Administration of anti-CTACK mAb (a) or control irrelevant antibody (not shown) had no effect on the percentage of adoptively transferred wild-type donor T cells (Thy1.2+) among skin CD4 cells (compared with panel a). In contrast, anti-CTACK dramatically inhibits skin homing of CCR4-deficient lymphocytes (b). Data are percentage of donor (Thy1.2+) T cells among CD4 T cells in each tissue, normalized to LN values (mean ± SEM of seven experiments). The proportion of donor Thy1.2+ CD4 cells among LN CD4 cells (which defines a relative localization of 100% in each experiment) ranged from 1 to 13%.

Figure 5.

Figure 5.

CCR4 and CTACK-dependent reduction of ear swelling in a cutaneous DTH reaction. Thy1.1 congenic recipients were treated with anti-CTACK mAb or the isotype control before the adoptive transfer of immunized Thy1.2+ donor LN cells. Recipient or control mouse ears were stimulated by local application of DNFB. Swelling induced by transferred CCR4−/− but not by wild-type immune T cells is blocked with a mAb against CTACK. Background swelling of DNFB treated recipients without donor cells has been subtracted (mean ± SEM of seven experiments).

Similar articles

Cited by

References

    1. Warnock, R.A., J.J. Campbell, M.E. Dorf, A. Matsuzawa, L.M. McEvoy, and E.C. Butcher. 2000. The role of chemokines in the microenvironmental control of T versus B cell arrest in Peyer's patch high endothelial venules. J. Exp. Med. 191:77–88. - PMC - PubMed
    1. Stein, J.V., A. Rot, Y. Luo, M. Narasimhaswamy, H. Nakano, M.D. Gunn, A. Matsuzawa, E.J. Quackenbush, M.E. Dorf, and U.H. von Andrian. 2000. The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules. J. Exp. Med. 191:61–76. - PMC - PubMed
    1. Pan, J., E.J. Kunkel, U. Gosslar, N. Lazarus, P. Langdon, K. Broadwell, M.A. Vierra, M.C. Genovese, E.C. Butcher, and D. Soler. 2000. A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues. J. Immunol. 165:2943–2949. - PubMed
    1. Kunkel, E.J., J.J. Campbell, G. Haraldsen, J. Pan, J. Boisvert, A.I. Roberts, E.C. Ebert, M.A. Vierra, S.B. Goodman, M.C. Genovese, et al. 2000. Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J. Exp. Med. 192:761–768. - PMC - PubMed
    1. Campbell, J.J., G. Haraldsen, J. Pan, J. Rottman, S. Qin, P. Ponath, D.P. Andrew, R. Warnke, N. Ruffing, N. Kassam, L. Wu, and E.C. Butcher. 1999. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature. 400:776–780. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources