Antigen processing and presentation of HLA class II restricted minor histocompatibility antigens

供体淋巴细胞输注可有效治疗hla匹配造血干细胞移植后复发的恶性血液病患者。供体来源的T细胞介导有益的移植物抗白血病（GvL）效应，但也可能诱导有害的移植物抗宿主病（GvHD）。这些T细胞反应是针对多态肽的，多态肽在患者和供体之间由于单核苷酸多态性而不同。这些次要组织相容性抗原（MiHA）由HLA I类或II类呈递，从而分别激活CD8+和CD4+ T细胞。我们最近发现了5个HLA II类限制性miha，它们在专业抗原呈递细胞（APC）上被识别，如B细胞、树突状细胞和白血病细胞。然而，所有的MiHA特异性CD4+ T细胞克隆都不能识别非造血细胞，尽管细胞因子显著上调HLA II类。此外，尽管表达了MiHA编码基因和HLA II类分子，但仍有有限数量的恶性造血细胞未被识别。我们推测，MiHA特异性CD4+ T细胞缺乏对非专业APC的识别可能是由于这些细胞无法正确处理并将MiHA呈递到HLA II类途径。本项目旨在揭示HLA II类限制性miha的抗原加工和递呈途径。造血细胞与非造血细胞中HLA II类加工的差异可用于选择性地刺激GvL反应性，而无需GvHD。此外，HLA II类抗原加工机制可能在造血分化的不同阶段有所不同，这也可能适用于来自不同谱系和分化阶段的白血病细胞。更好地了解HLA II类抗原加工和细胞内抗原呈递的机制，有助于更好地利用CD4+ T细胞为基础的免疫治疗。

Patients with relapsed hematological malignancies after HLA-matched hematopoietic stem cell transplantation can be effectively treated with donor lymphocyte infusion. Donor-derived T cells mediate beneficial graft-versus-leukemia (GvL) effect but may also induce detrimental graft-versus-host disease (GvHD). These T cell responses are directed against polymorphic peptides which differ between patient and donor due to single nucleotide polymorphisms. These minor histocompatibility antigens (MiHA) are presented by HLA class I or II, thereby activating CD8+ and CD4+ T cells, respectively. We recently identified five HLA class II restricted MiHAs that were recognized on professional antigen presenting cells (APC), such as B cells and dendritic cells, and leukemic cells. However, all MiHA specific CD4+ T cell clones failed to recognize non-hematopoietic cells despite significant up-regulation of HLA class II by cytokines. In addition, a limited number of malignant hematopoietic cells was not recognized despite expression of the MiHA encoding gene and HLA class II molecules. We hypothesize that lack of recognition of non-professional APC by MiHA specific CD4+ T cells may be due to the failure of these cells to properly process and present the MiHAs into the HLA class II pathway. Aim of this project is to unravel the antigen processing and presentation pathways of HLA class II restricted MiHAs. Differential HLA class II processing in hematopoietic versus non-hematopoietic cells could be used to selectively stimulate GvL reactivity without GvHD. Moreover, HLA class II antigen processing mechanisms may vary between distinct stages of hematopoietic differentiation, which might also apply for leukemic cells derived from different lineages and differentiation stages. A better understanding of the mechanisms in HLA class II antigen processing and presentation of intracellular antigens is relevant to better exploit CD4+ T cell based immunotherapy.