Castellino F, Boucher P E, Eichelberg K, Mayhew M, Rothman J E, Houghton A N, Germain R N
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1892, USA.
J Exp Med. 2000 Jun 5;191(11):1957-64. doi: 10.1084/jem.191.11.1957.
Heat shock proteins (HSPs) derived from tumors or virally infected cells can stimulate antigen-specific CD8(+) T cell responses in vitro and in vivo. Although this antigenicity is known to arise from HSP-associated peptides presented to the immune system by major histocompatibility complex (MHC) class I molecules, the cell biology underlying this presentation process remains poorly understood. Here we show that HSP 70 binds to the surface of antigen presenting cells by a mechanism with the characteristics of a saturable receptor system. After this membrane interaction, processing and MHC class I presentation of the HSP-associated antigen can occur via either a cytosolic (transporter associated with antigen processing [TAP] and proteasome-dependent) or an endosomal (TAP and proteasome-independent) route, with the preferred pathway determined by the sequence context of the optimal antigenic peptide within the HSP-associated material. These findings not only characterize two highly efficient, specific pathways leading to the conversion of HSP-associated antigens into ligands for CD8(+) T cells, they also imply the existence of a mechanism for receptor-facilitated transmembrane transport of HSP or HSP-associated ligands from the plasma membrane or lumen of endosomes into the cytosol.
肿瘤或病毒感染细胞产生的热休克蛋白（HSPs）在体外和体内均可刺激抗原特异性CD8(+) T细胞反应。虽然已知这种抗原性源于主要组织相容性复合体（MHC）I类分子呈递给免疫系统的HSP相关肽，但该呈递过程背后的细胞生物学仍知之甚少。在此我们表明，HSP 70通过一种具有可饱和受体系统特征的机制与抗原呈递细胞表面结合。这种膜相互作用之后，HSP相关抗原的加工和MHC I类呈递可通过胞质途径（与抗原加工相关的转运体[TAP]和蛋白酶体依赖性）或内体途径（TAP和蛋白酶体非依赖性）发生，首选途径由HSP相关物质中最佳抗原肽的序列背景决定。这些发现不仅描述了两条高效、特异的途径，可导致HSP相关抗原转化为CD8(+) T细胞的配体，还暗示存在一种机制，可促进HSP或HSP相关配体从质膜或内体腔跨膜转运至胞质溶胶。
