Chemoattractant cytokines (chemokines) are important mediators of lymphocyte trafficking from the circulation into sites of tissue damage and inflammation, and into secondary lymphoid organs. Certain chemokines rapidly trigger lymphocyte integrins, causing increased avidity with endothelial ligands, resulting in arrest of the lymphocyte on endothelial cells close to the chemokine source. Gradients of chemokine molecules can also attract arrested cells through the endothelium and into the surrounding tissue. A variety of chemokines are differentially expressed in various tissue types, suggesting a role in the differential homing of specific lymphocyte subsets to various types of tissue. We have found (in the human system) that the chemokines TARC and MDC efficiently attract circulating systemic memory T cells, especially skin-homing T cells expressing the cutaneous lymphocyte antigen, CLA. In contrast, intestinal (a4B7+) memory and naive T cells respond poorly. Immunohistochemistry reveals anti-TARC reactivity with venules involved in lymphocyte trafficking in chronically inflamed skin, but not in the gastrointestinal lamina propria, suggesting a potential role in circulating CLA+ lymphocyte recognition of skin vasculature. Consistent with this, TARC triggers integrin-dependent adhesion of CLA+ (but not a4B7hi intestinal) memory T cells to ICAM-1; and mediates rapid integrin-dependent arrest of lymphocytes rolling on the vascular CLA receptor, E-selectin, under physiologic flow conditions. The results suggest a fundamental role for TARC and its lymphocyte receptor CCR4 in lymphocyte-endothelial cell recognition and in differential trafficking of lymphocyte populations responsible for systemic vs. intestinal immunity. In order to define this role in detail, here we shall characterize CCR4 expression and responsiveness to TARC and MDC among specialized subsets of lymphocytes in man (Aim 1). We will determine if the preferential effects of TARC and MDC on systemic vs. mucosal lymphocytes are also observed in the mouse, and will ask if these responses are CCR4-dependent (Aim 2). The availability of a mutant CCR4-deficient mouse line will allow us to explore the role of this receptor in targeted lymphocyte homing to inflamed skin (Aim 3) and its role in the inflammation process in models of DTH and autoimmune psoriasis (Aim 4). Monoclonal antibodies to mouse CCR4 and its ligands will facilitate these studies (Aim 5). These studies promise to define a critical component of lymphocyte recruitment to systemic sites inflammation, and may lead to novel therapeutic approaches in cutaneous (i.e. psoriasis) and other inflammatory diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Sawyer, Richard T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Children's Hospital Boston
United States
Zip Code
Vander Lugt, Bryan; Beck, Zachary T; Fuhlbrigge, Robert C et al. (2011) TGF-? suppresses ?-catenin-dependent tolerogenic activation program in dendritic cells. PLoS One 6:e20099
Oyoshi, Michiko K; Elkhal, Abdallah; Scott, Jordan E et al. (2011) Epicutaneous challenge of orally immunized mice redirects antigen-specific gut-homing T cells to the skin. J Clin Invest 121:2210-20
Tubo, Noah J; McLachlan, James B; Campbell, James J (2011) Chemokine receptor requirements for epidermal T-cell trafficking. Am J Pathol 178:2496-503
Campbell, James J; Clark, Rachael A; Watanabe, Rei et al. (2010) Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. Blood 116:767-71
Morgan, Angela J; Guillen, Cristina; Symon, Fiona A et al. (2008) CXCR6 identifies a putative population of retained human lung T cells characterised by co-expression of activation markers. Immunobiology 213:599-608
Campbell, James J; O'Connell, Daniel J; Wurbel, Marc-Andre (2007) Cutting Edge: Chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions. J Immunol 178:3358-62
Wurbel, Marc-Andre; Malissen, Marie; Guy-Grand, Delphine et al. (2007) Impaired accumulation of antigen-specific CD8 lymphocytes in chemokine CCL25-deficient intestinal epithelium and lamina propria. J Immunol 178:7598-606
Meyer, Everett H; Wurbel, Marc-Andre; Staton, Tracy L et al. (2007) iNKT cells require CCR4 to localize to the airways and to induce airway hyperreactivity. J Immunol 179:4661-71
Janowicz, Diane M; Tenner-Racz, Klara; Racz, Paul et al. (2007) Experimental infection with Haemophilus ducreyi in persons who are infected with HIV does not cause local or augment systemic viral replication. J Infect Dis 195:1443-51
Kivisakk, Pia; Tucky, Barbara; Wei, Tao et al. (2006) Human cerebrospinal fluid contains CD4+ memory T cells expressing gut- or skin-specific trafficking determinants: relevance for immunotherapy. BMC Immunol 7:14

Showing the most recent 10 out of 12 publications