Böhm Verena, Podlech Jürgen, Thomas Doris, Deegen Petra, Pahl-Seibert Marcus-Folker, Lemmermann Niels A W, Grzimek Natascha K A, Oehrlein-Karpi Silke A, Reddehase Matthias J, Holtappels Rafaela
Institute for Virology, Johannes Gutenberg-University, Obere Zahlbacher Strasse 67, Hochhaus am Augustusplatz, 55131 Mainz, Germany.
Med Microbiol Immunol. 2008 Jun;197(2):135-44. doi: 10.1007/s00430-008-0092-3. Epub 2008 Mar 14.
Preclinical research in murine models as well as subsequent clinical trials have concordantly revealed a high protective potential of antiviral CD8 T cells, of donor-derived ex vivo memory CD8 T cells in particular, in the immunotherapy of cytomegalovirus (CMV) infection in immunocompromised recipients. Although it is generally held view that the observed beneficial effect of the transferred cells is viral epitope-specific, involving the recognition of MHC class-I presented peptides by cognate T cell receptors, this assumption awaits formal proof, at least with regard to the in vivo function of the CD8 T cells. This question is particularly evident for CMV, since the function of viral immune evasion proteins interferes with the MHC class-I pathway of peptide presentation. Alternatively, therefore, one has to consider the possibility that the requirement for epitope recognition may be bypassed by other ligand-receptor interactions between CD8 T cells and infected cells, which may trigger the signaling for effector functions. Clearly, such a mechanism might explain why CD8 T cells are so efficient in controlling CMV infection despite the expression of viral immune evasion proteins. Here we provide direct evidence for epitope-specificity of antiviral protection by employing a recombinant murine CMV (mCMV), namely the mutant virus mCMV-IE1-L176A, in which an immunodominant viral epitope of the regulatory immediate-early protein IE1 is functionally deleted by a point mutation replacing leucine with alanine at the C-terminal MHC anchor position of the antigenic peptide.
在小鼠模型中的临床前研究以及随后的临床试验一致表明，抗病毒CD8 T细胞，特别是供体来源的体外记忆CD8 T细胞，在免疫受损受体的巨细胞病毒（CMV）感染免疫治疗中具有很高的保护潜力。尽管人们普遍认为，所观察到的转移细胞的有益作用是病毒表位特异性的，涉及同源T细胞受体对MHC I类呈递肽的识别，但这一假设至少在CD8 T细胞的体内功能方面仍有待正式证实。对于CMV来说，这个问题尤为明显，因为病毒免疫逃避蛋白的功能会干扰肽呈递的MHC I类途径。因此，另一种可能性是，CD8 T细胞与受感染细胞之间的其他配体-受体相互作用可能绕过表位识别的要求，从而触发效应功能的信号传导。显然，这样一种机制可能解释了为什么尽管存在病毒免疫逃避蛋白的表达，CD8 T细胞在控制CMV感染方面仍如此有效。在这里，我们通过使用重组小鼠巨细胞病毒（mCMV），即突变病毒mCMV-IE1-L176A，提供了抗病毒保护表位特异性的直接证据，在该突变病毒中，调节性立即早期蛋白IE1的一个免疫显性病毒表位在抗原肽的C末端MHC锚定位点通过将亮氨酸替换为丙氨酸的点突变而功能缺失。
