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/jci14843
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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
观察到TCR、BCR和一些Fc受体与多个itam信号亚基相关，表明这些亚基支持受体参与时有效的信号放大。另外，不同的含itam亚基的配对可以允许激活的受体通过结合不同的含SH2结构域的效应分子以模块化的方式连接到特定的下游信号通路。ITAM受体中研究得最透彻的可能是TCR复合物，它由一对抗原识别链（αβ或γδ）、CD3链（εγ和εδ）和一对同二聚体ζ链组成（图1）。总的来说，TCR复合物包含10个itam，每个来自CD3链，6个来自ζ二聚体。相比之下，其他含有itam的受体每个都有2到4个itam。CD3和ζ链在调节T细胞发育中的作用已经确定，我们推荐Love和Shores(9)最近对这一主题的综述。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一个或多个这些序列的ζ链转导到TCR转基因的ζ链缺陷小鼠中。在所有情况下，来自ζ链重组动物的外周T细胞似乎仍然可以通过TCR被激活（参见参考文献）。9,10)，这表明存在于CD3链中的itam足以实现这一过程。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（参见文献6），这意味着通过这些不同的基序有可能激活不同的信号级联反应。因此，正如Sommers等人所指出的，将itam突变型CD3ε亚基放入CD3ε缺陷小鼠中，不像野生型亚基那样支持T细胞存活，至少在转基因TCR小鼠系中是这样（11）。这些作者还发现，T细胞成熟似乎正常，这表明，正如在ζ链ITAM缺陷的动物中所看到的那样，功能性CD3ε ITAM的缺失导致了对TCR信号的定量而非定性影响（11）。最近的一项研究表明，在cd3 δ缺陷小鼠的T细胞中，不能进行正常的阳性选择，tcr诱导的脂筏组分中的ζ链磷酸化和细胞外信号调节激酶（ERK）激活是有缺陷的。有趣的是，这两个事件都可以在引入CD3δ亚基后重建，不仅缺乏ITAM，而且缺乏整个细胞质结构域（12）。与这一发现一致，与CD3δ相关的TCRα结构域的突变阻碍了阳性选择(7)。因此，除了它们对TCR信号传导的贡献外，CD3亚基还可以通过非itam结构域来检测或影响配体结合过程中发生的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.