Kazansky Dmitry B
N. N. Blokhin's Cancer Research Center, Carcinogenesis Institute, Moscow, Russia.
J Immunotoxicol. 2008 Oct;5(4):369-84. doi: 10.1080/15476910802476708.
Discovery of major histocompatability complex (MHC) restriction helped in the understanding of how T-lymphocytes recognize antigens on bacteria, viruses, and tumor cells. It was initially accepted that MHC restriction was a consequence of "adaptive differentiation" in the thymus; during differentiation, the forming repertoire of T-lymphocytes "learned" a low affinity for self MHC molecules via positive selection. This view was later countered by discovery of artifacts in underlying studies and the fact that adaptive differentiation could not explain direct allogeneic and allorestricted recognition phenomena. Data from experiments with TCR transgenic animals, individual MHC/peptide complex expression, and recipients of xenogenic thymus glands yielded evidence of an ability to adapt to microenvironment and a low specificity of positive selection. These facts led to an alternative interpretation of MHC restriction explained, in part, by specificity of a pool of effector cells activated by primary immunization. Details of this phenomenon were defined in studies that noted differential primary structures of peptides that bound various allelic forms of MHC molecules. Here, the T-lymphocyte repertoire formed in the thymus was a result, in part, of random rearrangement of germinal sequences of TCR gene fragments. Such pre-selected repertoires were inherently capable of reacting with different allelic forms of MHC molecules. In contrast, MHC molecules were characterized by significant intraspecies polymorphisms; negative and positive selections were aimed at adaptation of a pre-selected repertoire to a specific microenvironment in an individual. Via elimination of autoreactive clones and sparing of a broad spectrum of specificity to potential pathogens, selection in the thymus could be considered a life-long allogeneic reaction of a pre-selected repertoire to self MHC molecules resulting in tolerance to "self," increased responsiveness to foreign MHC molecules, and cross-reactivity of the mature T-lymphocyte repertoire to individual foreign peptides plus self MHC.
主要组织相容性复合体（MHC）限制的发现有助于理解T淋巴细胞如何识别细菌、病毒和肿瘤细胞上的抗原。最初人们认为MHC限制是胸腺中“适应性分化”的结果；在分化过程中，T淋巴细胞形成的库通过阳性选择“学会”了对自身MHC分子的低亲和力。后来，这一观点被基础研究中发现的假象以及适应性分化无法解释直接同种异体和同种异体限制识别现象这一事实所反驳。来自TCR转基因动物实验、个体MHC/肽复合物表达以及异种胸腺移植受体的数据表明，存在适应微环境的能力以及阳性选择的低特异性。这些事实导致了对MHC限制的另一种解释，部分原因是初次免疫激活的效应细胞库的特异性。这一现象的细节在研究中得以明确，这些研究指出了与MHC分子不同等位基因形式结合的肽的不同一级结构。在这里，胸腺中形成的T淋巴细胞库部分是TCR基因片段胚系序列随机重排的结果。这种预先选择的库天生就能够与MHC分子的不同等位基因形式发生反应。相比之下，MHC分子具有显著的种内多态性；阴性和阳性选择旨在使预先选择的库适应个体中的特定微环境。通过消除自身反应性克隆并保留对潜在病原体的广泛特异性，胸腺中的选择可被视为预先选择的库对自身MHC分子的终身同种异体反应，从而导致对“自身”的耐受性增加、对外来MHC分子的反应性增强以及成熟T淋巴细胞库对单个外来肽加自身MHC的交叉反应性。
