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J. Biol. Chem., Vol. 276, Issue 20, 17455-17460, May 18, 2001

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Functional Uncoupling of T-cell Receptor Engagement and Lck Activation in Anergic Human Thymic CD4⁺ T Cells^*

Wakae Fujimaki^§, Makio Iwashima^¶, Junji Yagi, Hua Zhang, Hisako Yagi, Kazuhiro Seo, Yasuharu Imai, Ken'ichi Imanishi, and Takehiko Uchiyama

From the  Department of Microbiology and Immunology and  Department of Pediatric Cardiovascular Surgery, The Heart Institute of Japan, Tokyo Women's Medical University, Tokyo 162-8666, Japan and the ^¶ Program in Molecular Immunology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912-2600

Human thymic CD1aCD4⁺ T cells in the final stage of thymic maturation are susceptible to anergy induced by a superantigen, toxic shock syndrome toxin-1 (TSST-1). Thymic CD4⁺ T-cell blasts, established by stimulating human thymic CD1aCD4⁺ T cells with TSST-1 in vitro, produce a low level of interleukin-2 after restimulation with TSST-1, whereas TSST-1-induced adult peripheral blood (APB) CD4⁺ T-cell blasts produce high levels of interleukin-2. The extent of tyrosine phosphorylation of the T-cell receptor  chain induced after restimulation with TSST-1 was 2-4-fold higher in APB CD4⁺ T-cell blasts than in thymic CD4⁺ T-cell blasts. The tyrosine kinase activity of Lck was low in both thymic and APB CD4⁺ T-cell blasts before restimulation with TSST-1. After restimulation, the Lck kinase activity increased in APB CD4⁺ T-cell blasts but not in thymic CD4⁺ T-cell blasts. Surprisingly, Lck was highly tyrosine-phosphorylated in both thymic and APB CD4⁺ T-cell blasts before restimulation with TSST-1. After restimulation, it was markedly dephosphorylated in APB CD4⁺ T-cell blasts but not in thymic CD4⁺ T-cell blasts. Lck from APB CD4⁺ T-cell blasts bound the peptide containing the phosphotyrosine at the negative regulatory site of Lck-505 indicating that the site of dephosphorylation in TSST-1-activated T-cell blasts is Tyr-505. Confocal microscopy demonstrated that colocalization of Lck and CD45 was induced after restimulation with TSST-1 in APB CD4⁺ T-cell blasts but not in thymic CD4⁺ T-cell blasts. Further, remarkable accumulation of Lck in the membrane raft was observed in restimulated APB CD4⁺ T-cell blasts but not in thymic CD4⁺ T-cell blasts. These data indicate that interaction between Lck and CD45 is suppressed physically in thymic CD4⁺ T-cell blasts and plays a critical role in sustaining an anergic state.

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