Babbitt B P, Allen P M, Matsueda G, Haber E, Unanue E R
Nature. 1985;317(6035):359-61. doi: 10.1038/317359a0.
Most cellular interactions essential for the development of an immune response involve the membrane glycoproteins encoded in the major histocompatibility gene complex. The products of the I region, the class II histocompatibility molecules (Ia molecules), are essential for accessory cells such as macrophages to present polypeptide antigens to helper T cells. This interaction, antigen presentation, is needed for T-cell recognition of the antigen and its consequent activation. How the Ia molecules regulate the immune response during antigen presentation is not known, although it is commonly thought to result from their association with the presented antigen. Recent studies, including the elucidation of the structure of the T-cell receptor, favour recognition of a single structure, an antigen-Ia complex. Here we report attempts to determine whether purified Ia glycoproteins have an affinity for polypeptide antigens presented by intact cells in an Ia-restricted manner. We first identified the epitope of a peptide antigen involved in presentation. Several laboratories have shown that globular proteins are altered (processed) in intracellular vesicles of the antigen-presenting cell before antigen presentation. A major component of the T-cell response is directed toward determinants found in the unfolded or denatured molecule, and our laboratory has shown that the determinant of the hen-egg lysozyme protein (HEL), presented in H-2k mice to T cells, is a sequence of only 10 amino acids. This portion resides in an area of the native molecule partially buried inside the molecule, in a beta-sheet conformation. To be presented, intact or native HEL must first be processed in acidic intracellular vesicles. Having isolated the peptide responsible for T-cell recognition of HEL, we sought a physical association of this peptide with purified, detergent-solubilized I-Ak molecules from B-hybridoma cells. We have found such an association, which may explain the role of the Ia glycoproteins in cellular interactions.
免疫应答发育所必需的大多数细胞间相互作用都涉及主要组织相容性基因复合体中编码的膜糖蛋白。I区的产物，即II类组织相容性分子（Ia分子），对于诸如巨噬细胞等辅助细胞将多肽抗原呈递给辅助性T细胞至关重要。这种相互作用，即抗原呈递，是T细胞识别抗原及其随后激活所必需的。尽管通常认为Ia分子在抗原呈递过程中调节免疫应答是由于它们与呈递的抗原结合，但具体机制尚不清楚。包括T细胞受体结构阐明在内的近期研究倾向于认为存在一种单一结构，即抗原-Ia复合体。在此，我们报告了关于确定纯化的Ia糖蛋白是否以Ia限制的方式对完整细胞呈递的多肽抗原具有亲和力的尝试。我们首先鉴定了参与呈递的肽抗原的表位。几个实验室已经表明，球状蛋白在抗原呈递之前在抗原呈递细胞的细胞内囊泡中会发生改变（加工）。T细胞应答的一个主要成分是针对未折叠或变性分子中发现的决定簇，并且我们实验室已经表明，在H-2k小鼠中呈递给T细胞的鸡卵溶菌酶蛋白（HEL）的决定簇是仅由10个氨基酸组成的序列。该部分位于天然分子中部分埋在分子内部的区域，呈β-折叠构象。为了被呈递，完整的或天然的HEL必须首先在酸性细胞内囊泡中进行加工。在分离出负责T细胞识别HEL的肽后，我们寻求该肽与来自B杂交瘤细胞的纯化的、去污剂溶解的I-Ak分子之间的物理结合。我们发现了这样一种结合，这可能解释了Ia糖蛋白在细胞间相互作用中的作用。
