title: An abortive ligand-induced activation of CCR1-mediated downstream signaling event and a deficiency of CCR5 expression are associated with the hyporesponsiveness of human naive CD4+ T cells to CCL3 and CCL5.
abstract: Human memory CD4(+) T cells respond better to inflammatory CCLs/CC chemokines, CCL3 and CCL5, than naive CD4(+) T cells. We analyzed the regulatory mechanism underlying this difference. Memory and naive CD4(+) T cells expressed similarly high levels of CCR1; however, CCR5 was only expressed in memory CD4(+) T cells at low levels. Experiments using mAbs to block chemokine receptors revealed that CCR1 functioned as a major receptor for the binding of CCL5 in memory and naive CD4(+) T cells as well as the ligand-induced chemotaxis in memory CD4(+) T cells. Stimulation of memory CD4(+) T cells with CCL5 activated protein tyrosine kinase-dependent cascades, which were significantly blocked by anti-CCR1 mAb, whereas this stimulation failed to induce these events in naive CD4(+) T cells. Intracellular expressions of regulator of G protein signaling 3 and 4 were only detected in naive CD4(+) T cells. Pretreatment of cell membrane fractions from memory and naive CD4(+) T cells with GTP-gamma S inhibited CCL5 binding, indicating the involvement of G proteins in the interaction of CCL5 and its receptor(s). In contrast, CCL5 enhanced the GTP binding to G(i alpha) and G(q alpha) in memory CD4(+) T cells, but not in naive CD4(+) T cells. Thus, a failure of the ligand-induced activation of CCR1-mediated downstream signaling event as well as a deficiency of CCR5 expression may be involved in the hyporesponsiveness of naive CD4(+) T cells to CCL3 and CCL5.
authors.affiliation: Department of Immunology and Medical Zoology, School of Medicine, Kagoshima University, Sakuragaoka, Kagoshima, Japan. katusaki@m3.kufm.kagoshima-u.ac.jp
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Sato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawasaki
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
authors.forename: Naohide
authors.initials: N
authors.lastname: Yamashima
authors.forename: Takami
authors.initials: T
authors.lastname: Matsuyama
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000096:biosynthesis; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology; D007399:Interphase / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins / Q000502:physiology*; D011485:Protein Binding / Q000276:immunology; D020710:RGS Proteins / Q000096:biosynthesis; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000172:deficiency* / Q000378:metabolism; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: C515300:CCR1 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D008024:Ligands; D019402:Macrophage Inflammatory Proteins; D020710:RGS Proteins; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D020962:Heterotrimeric GTP-Binding Proteins