Norment A M, Forbush K A, Nguyen N, Malissen M, Perlmutter R M
Department of Immunology, University of Washington, Seattle 98195, USA.
J Exp Med. 1997 Jan 6;185(1):121-30. doi: 10.1084/jem.185.1.121.
An important checkpoint in early thymocyte development ensures that only thymocytes with an in-frame T cell receptor for antigen beta (TCR-beta) gene rearrangement will continue to mature. Proper assembly of the TCR-beta chain into the pre-TCR complex delivers signals through the src-family protein tyrosine kinase p56lck that stimulate thymocyte proliferation and differentiation to the CD4+CD8+ stage. However, the biochemical mechanisms governing p56lck activation remain poorly understood. In more mature thymocytes, p56lck is associated with the cytoplasmic domain of the TCR coreceptors CD4 and CD8, and cross-linking of CD4 leads to p56lck activation. To study the effect of synchronously inducing p56lck activation in immature CD4-CD8- thymocytes, we generated mice expressing a CD4 transgene in Rag2-/- thymocytes. Remarkably, without further experimental manipulation, the CD4 transgene drives maturation of Rag2-/- thymocytes in vivo. We show that this process is dependent upon the ability of the CD4 transgene to bind Lck and on the expression of MHC class II molecules. Together these results indicate that binding of MHC class II molecules to CD4 can deliver a biologically relevant, Lck-dependent activation signal to thymocytes in the absence of the TCR-alpha or -beta chain.
早期胸腺细胞发育中的一个重要检查点可确保只有那些抗原β（TCR-β）基因重排读框正确的胸腺细胞才能继续成熟。TCR-β链正确组装到前TCR复合物中会通过src家族蛋白酪氨酸激酶p56lck传递信号，刺激胸腺细胞增殖并分化至CD4⁺CD8⁺阶段。然而，调控p56lck激活的生化机制仍知之甚少。在更成熟的胸腺细胞中，p56lck与TCR共受体CD4和CD8的胞质结构域相关联，CD4的交联会导致p56lck激活。为了研究在未成熟的CD4⁻CD8⁻胸腺细胞中同步诱导p56lck激活的效果，我们构建了在Rag2⁻/⁻胸腺细胞中表达CD4转基因的小鼠。值得注意的是，无需进一步的实验操作，CD4转基因就能在体内驱动Rag2⁻/⁻胸腺细胞成熟。我们发现这个过程依赖于CD4转基因结合Lck的能力以及MHC II类分子的表达。这些结果共同表明，在没有TCR-α或-β链的情况下，MHC II类分子与CD4的结合能够向胸腺细胞传递生物学上相关的、依赖Lck的激活信号。
