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Cross-Linking of 4-1BB Activates TCR-Signaling Pathways in CD8⁺ T Lymphocytes¹

Kyung-Ok Nam, Hyun Kang, Su-Mi Shin, Kwang-Hyun Cho, Byoungsuk Kwon, Byoung S. Kwon, Sung-Jin Kim^* and Hyeon-Woo Lee^2,*,

^* Department of Pharmacology, School of Dentistry, Kyung Hee University, Seoul, Korea; Immunomodulation Research Center and Graduate Program in Immunology and Biomedicine, University of Ulsan, Ulsan, Korea; and College of Medicine and Korea Bio-MAX Center, Seoul National University, Seoul, Korea;

Cross-linking of 4-1BB, a member of the TNFR family, increased tyrosine phosphorylation of TCR-signaling molecules such as CD3, CD3, Lck, the linker for activation of T cells, and SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76). In addition, incubation of activated CD8⁺ T cells with p815 cells expressing 4-1BBL led to redistribution of the lipid raft domains and Lck, protein kinase C-, SLP-76, and phospholipase C-1 (PLC-1) on the T cell membranes to the areas of contact with the p815 cells and recruitment of 4-1BB, TNFR-associated factor 2, and phospho-tyrosine proteins to the raft domains. 4-1BB ligation also caused translocation of TNFR-associated factor 2, protein kinase C-, PLC-1, and SLP-76 to detergent-insoluble compartments in the CD8⁺ T cells, and cross-linking of 4-1BB increased intracellular Ca²⁺ levels apparently by activating PLC-1. The redistribution of lipid rafts and Lck, as well as translocation of PLC-1, and degradation of IB- in response to 4-1BB were inhibited by disrupting the formation of lipid rafts with methyl--cyclodextrin. These findings demonstrate that 4-1BB is a T cell costimulatory receptor that activates TCR-signaling pathways in CD8⁺ T cells.

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