The relative activity of CXCR3 and CCR5 ligands in T lymphocyte migration: concordant and disparate activities in vitro and in vivo.
In chronic inflammatory reactions such as rheumatoid arthritis and multiple sclerosis, T cells in the inflamed tissue express the chemokine receptors CXCR3 and CCR5, and the chemokine ligands (CCL) of these receptors are present in the inflammatory lesions. However, the contribution of these chemokines to T cell recruitment to sites of inflammation is unclear. In addition, the relative roles of the chemokines that bind CXCR3 (CXCL9, CXCL10, CXCL11) and CCR5 (CCL3, CCL4, CCL5) in this process are unknown. The in vitro chemotaxis and in vivo migration of antigen-activated T lymphoblasts and unactivated spleen T cells to chemokines were examined. T lymphoblasts migrated in vitro to CXCR3 ligands with a relative potency of CXCL10 > CXCL11 > CXCL9, but these cells demonstrated much less chemotaxis to the CCR5 ligands. In vivo, T lymphocytes were recruited in large numbers with rapid kinetics to skin sites injected with CXCL10 and CCL5 and less to CCL3, CCL4, CXCL9, and CXCL11. The combination of CCL5 with CXCL10 but not the other chemokines markedly increased recruitment. Coinjection of interferon-gamma, tumor necrosis factor alpha, and interleukin-1alpha to up-regulate endothelial cell adhesion molecule expression with CXCL10 or CCL5 induced an additive increase in lymphoblast migration. Thus, CXCR3 ligands are more chemotactic than CCR5 ligands in vitro; however, in vivo, CXCL10 and CCL5 have comparable T cell-recruiting activities to cutaneous sites and are more potent than the other CXCR3 and CCR5 chemokines. Therefore, in vitro chemotaxis induced by these chemokines is not necessarily predictive of their in vivo lymphocyte-recruiting activity.
Stanford
Marianne M
MM
Departments of Microbiology & Immunology, Dalhousie University Avenue, Halifax, Nova Scotia, Canada.
Issekutz
Thomas B
TB
D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D018925:Chemokines / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D008214:Lymphocytes / Q000276:immunology / Q000502:physiology*; D019713:Receptors, CCR5 / Q000502:physiology*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000502:physiology*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*
C515187:CXCR3 protein, human; D018925:Chemokines; D016207:Cytokines; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine