The pathway for MHU-mediated presentation of endogenous proteins involves peptide transport to the endo-lysosomal compartment
The pathway for MHU-mediated presentation of endogenous proteins involves peptide transport to the endo-lysosomal compartment
复制标题
DOI：
10.1242/jcs.01288
复制
发表时间：
2004-08-15
影响因子：
4
通讯作者：
Mayor, S
中科院分区：
文献类型：
--
作者：
Dani, A;Chaudhry, A;Mayor, S
抗原提呈细胞（APC）通过主要组织相容性复合体（MHC）II类分子将内吞蛋白质的肽提呈给T细胞。然而，大部分从MHCII分子纯化的肽衍生自胞质自身蛋白，使得胞质肽加载到MHCII上的途径在免疫自身耐受的调节中具有关键相关性。我们表明，来自细胞质蛋白质的肽，无论是在细胞质中引入或表达，首先可检测到作为MHCII-肽复合物在LAMP-1（+）溶酶体，在其交付到细胞表面。这些肽-MHC复合物在多种APC中形成，包括腹膜巨噬细胞、树突细胞和B细胞，并且能够激活T细胞。这个过程需要不变链（Ii）依赖性分选MHCII的溶酶体和活性的分子伴侣H-2 M。该途径独立于ER驻留肽转运蛋白复合物TAP，并且不通过邻近细胞的交叉呈递而发生。结合我们早期的结果表明，这些肽是通过蛋白酶体的胞质加工衍生的，这些观察结果为肽转运到溶酶体中的普遍存在的途径提供了证据，以有效地将内源性和细胞质蛋白呈递给CD 4 T细胞。
Antigen-presenting cells (APCs) are expected to present peptides from endocytosed proteins via major histocompatibility complex (MHC) class II (MHCII) molecules to T cells. However, a large proportion of peptides purified from MHCII molecules are derived from cytosolic self-proteins making the pathway of cytosolic peptide loading onto MHCII of critical relevance in the regulation of immune self-tolerance. We show that peptides derived from cytoplasmic proteins either introduced or expressed in the cytoplasm are first detectable as MHCII-peptide complexes in LAMP-1(+) lysosomes, prior to their delivery to the cell surface. These peptide-MHC complexes are formed in a variety of APCs, including peritoneal macrophages, dendritic cells, and B cells, and are able to activate T cells. This process requires invariant chain (Ii)-dependent sorting of MHCII to the lysosome and the activity of the molecular chaperone H-2M. This pathway is independent of the ER resident peptide transporter complex TAP and does not take place by cross-presentation from neighbouring cells. In conjunction with our earlier results showing that these peptides are derived by cytosolic processing via the proteasome, these observations provide evidence for a ubiquitous route for peptide transport into the lysosome for the efficient presentation of endogenous and cytoplasmic proteins to CD4 T cells.