ANTIGEN PRESENTATION BY CLASS IB MOLECULE, QA-1

Qa-1/HLA-E在NK细胞上呈现与CD/NKG2受体非常相似的I类先导衍生肽。CD94/NKG2受体似乎是MHC限制性的，因为它们既识别Ib类分子，也识别特定的肽。因此，先导衍生肽的呈现对于靶细胞触发NK细胞上受体的能力至关重要。来自d区分子的小鼠肽的产生，我们称之为Qdm，以及来自HLA分子的Qdm样肽的产生，都是tap依赖的。我们之前已经证明，1)从成熟的Dd分子中加工Qdm肽与蛋白酶体活性无关，2)表位不能通过将Dd引导到细胞质中来产生，3)Tap的功能是将肽从细胞质转运到内质网，而不是作为内质网中肽装载的辅助分子。关于Qdm的处理，我们将解决几个问题。这包括确定由E3/19K先导蛋白靶向内质网的Dd先导蛋白是否可以在这个隔室中加工，改变先导蛋白n区的变化是否会改变其细胞内运输，蛋白酶在这一过程中的作用，以及侧翼残基如何影响加工。据报道，其他先导衍生的表位是由ⅰ类分子在tap缺陷T2细胞中呈现的。这个问题将通过检查这些表位在其他细胞类型中的呈现来解决。MHV和HCMV这两种病毒具有编码Qdm或Qdm样表位的基因。我们将确定这些病毒基因以及完整的病毒是否允许在感染细胞中表达Qdm。如果发生这种情况，我们将检查这些病毒编码的Qdm表位的加工和呈现。

Qa-1/HLA-E present very similar class I leader-derived peptides to CD/NKG2 receptors on NK cells. CD94/NKG2 receptors appear to be MHC restricted in that they recognize both the class Ib molecule as well as specific peptides. Thus, the presentation of the leader derived peptide is critical for the ability of target cells to trigger receptors on NK cells. The generation of the murine peptide from D-region molecules, which we refer to as Qdm, as well as the Qdm-like peptide from HLA molecules, as Tap-dependent. We have previously shown that 1)processing of the Qdm peptide from mature Dd molecules is independent of proteasome activity, 2) the epitope cannot be generated by directing Dd to the cytosol, and 3) Tap functions to transport the peptide from the cytosol to the ER rather than serving as an accessory molecule for peptide loading in the ER. There are several issues that we will address concerning the processing of Qdm. This includes determining whether the Dd leader targeted to the ER by the E3/19K leader can be processed in this compartment, whether altering the change in the N-region of the leader changes its intracellular trafficking, the role of proteases in this process, and how flanking residues affect processing. Other leader derived epitopes have been reported to be presented by class I molecules in Tap-deficient T2 cells. This issue will be addressed by examining the presentation of these epitopes in other cell types. Two viruses, MHV and HCMV, have genes which encode Qdm or Qdm-like epitopes. We will determine whether these viral genes, as well as the intact viruses, allow for Qdm expression in infected cells. If this occurs, we will then examine the processing and presentation of these viral encoded Qdm epitopes.