ITAMs versus ITIMs: striking a balance during cell regulation
ITAMs versus ITIMs: striking a balance during cell regulation
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DOI：
10.1172/jci200214843
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发表时间：
2002-01-01
影响因子：
15.9
通讯作者：
Leibson, PJ
中科院分区：
文献类型：
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作者：
Billadeau, DD;Leibson, PJ
TCR、BCR和一些Fc受体与多个ITAM信号传导亚基相关的观察结果表明，这些亚基支持受体接合后的有效信号放大。另外，不同的含ITAM亚基的配对可以允许活化的受体通过结合不同的含SH 2结构域的效应分子以模块化方式连接到特定的下游信号传导通路。CD3链（εγ和εδ）和CD4链的同源二聚体对（图1）。总的来说，TCR复合物含有10个ITAM，每个CD3链有一个ITAM，6个ITAM来自CD3二聚体。相比之下，其他含有ITAM的受体各自具有2至4个ITAM。CD3和CD4链在调节T细胞发育中的作用已经得到了牢固的确立，我们推荐Love和Shores最近对该主题的综述（9）。为了探索这些ITAM在TCR功能中的作用，几个研究小组已经将缺乏这些序列中的一个或多个的β链转导到TCR转基因β链缺陷小鼠中。在所有情况下，来自β链重建动物的外周T细胞似乎仍然可以通过TCR活化（参考文献10）。9，10），表明存在于CD3链中的ITAM足以用于该过程。事实上，已经发现不同的CD3链ITAM在体外与不同的底物相互作用（在参考文献6中综述），这意味着通过这些不同的基序激活不同的信号级联有一定的潜力。因此，正如Sommers等人所指出的，至少在研究的转基因TCR小鼠系中，置于CD3ε缺陷小鼠中的ITAM突变型CD3ε亚基不像野生型亚基那样支持T细胞存活（11）。这些作者还发现，T细胞成熟似乎正常，这表明，如在β链ITAM缺陷动物中所见，功能性CD3ε ITAM的丧失导致对TCR信号传导的定量而非定性影响（11）。最近的一项研究表明，在来自CD3δ缺陷小鼠的T细胞中，不能进行正常的阳性选择，TCR诱导的脂筏组分内的β链磷酸化和细胞外信号调节激酶（ERK）活化是有缺陷的。有趣的是，这两种事件都可以在引入CD3δ亚基后重建，该亚基不仅缺乏ITAM，而且缺乏整个胞质结构域（12）。与这一发现一致，与CD3δ结合所需的TCRα结构域突变阻断了阳性选择（7）。因此，除了它们对TCR信号传导的贡献之外，CD3亚基还可以通过非ITAM结构域起作用以检测或影响配体结合期间发生的TCR构象变化。
The observation that the TCR, BCR, and some Fc receptors are associated with multiple ITAM-signaling subunits suggests that these subunits support the efficient signal amplification upon receptor engagement. Alternatively, the pairing of distinct ITAM-containing subunits could allow activated receptors to link in a modular manner to specific downstream signaling pathways by binding to distinct SH2 domain–containing effector molecules.Probably the most thoroughly studied of the ITAM containing-receptors is the TCR complex, consisting of a pair of antigen-recognizing chains (αβ or γδ), the CD3 chains (εγ and εδ), and a homodimeric pair of ζ chains (Figure 1). In total, the TCR complex contains ten ITAMs, one from each of the CD3 chains and six from the ζ dimer. By contrast, other ITAM-containing receptors have two to four ITAMs each. The role of the CD3 and ζ chains in regulating T cell development has been firmly established, and we recommend the recent review by Love and Shores (9) on this subject. To explore the role of these ITAMs in TCR function, several groups have transduced ζ chains lacking one or more of these sequences into TCR transgenic, ζ chain–deficient mice. In all cases, it appears that peripheral T cells from the ζ chain–reconstituted animals can still be activated through the TCR (reviewed in refs. 9, 10), suggesting that ITAMs present in the CD3 chains are sufficient for this process. Indeed, different CD3 chain ITAMs have been found to interact with distinct substrates in vitro (reviewed in ref. 6), implying that there is some potential for activating distinct signaling cascades through these various motifs. Thus, as Sommers et al. have noted, ITAM-mutant CD3ε subunits placed into CD3ε-deficient mice do not support T cell survival as the wild-type subunit does, at least in the transgenic TCR mouse line studied (11). These authors also found that T cell maturation appeared normal, suggesting that, as was seen in ζ chain ITAM-deficient animals, the loss of a functional CD3ε ITAM leads to a quantitative but not a qualitative effect on TCR signaling (11). A recent study has shown that in T cells from CD3δ-deficient mice, which fail to undergo normal positive selection, TCR-induced ζ chain phosphorylation within lipid raft fractions and extracellular signal–regulated kinase (ERK) activation are defective. Interestingly, both events can be reconstituted following introduction of a CD3δ subunit lacking not just its ITAM but its entire cytoplasmic domain (12). Consistent with this finding, mutation of a TCRα domain required for association with CD3δ blocks positive selection (7). Therefore, in addition to their contribution to TCR signaling, the CD3 subunits may also act through non-ITAM domains to detect or influence TCR conformational changes occurring during ligand binding.