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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 CCL5¹

Katsuaki Sato^2,*, Hiroshi Kawasaki, Chikao Morimoto, Naohide Yamashima and Takami Matsuyama^*

^* Department of Immunology and Medical Zoology, School of Medicine, Kagoshima University, Sakuragaoka, Kagoshima, Japan; Department of Clinical Immunology and AIDS Research Center, and Department of Advanced Medical Science, Institute of Medical Science, University of Tokyo, Tokyo, Japan

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-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 and G_q 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.

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