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

供者淋巴细胞输注可有效治疗人类白细胞抗原相合的造血干细胞移植后复发的恶性血液病。供者来源的T细胞介导有益的移植物抗白血病(GVL)效应，但也可能诱发有害的移植物抗宿主病(GvHD)。这些T细胞反应针对的是多态多肽，由于单核苷酸多态，患者和捐赠者之间存在差异。这些次要组织相容性抗原(MIHA)由人类白细胞抗原I或II类递呈，从而分别激活CD8+和CD4+T细胞。我们最近发现了5种可在专业抗原提呈细胞(APC)上识别的HLAII类限制性MIHAs，如B细胞、树突状细胞和白血病细胞。然而，所有MIHA特异性的CD4+T细胞克隆都无法识别非造血细胞，尽管细胞因子显著上调了人类白细胞抗原II类。此外，尽管表达了MIHA编码基因和HLAII类分子，但仍有少量的恶性造血细胞未被识别。我们推测，MIHA特异性的CD4+T细胞不能识别非专业性APC可能是由于这些细胞不能正确地处理MIHAS并将其呈递到HLAII类途径中。本项目的目的是揭示人类白细胞抗原II类限制性MIHAS的抗原处理和提呈途径。造血细胞和非造血细胞对HLAII类的不同处理可用于选择性地刺激GVL反应性，而不需要GvHD。此外，在不同的造血分化阶段，人类白细胞抗原II类抗原的处理机制可能不同，这可能也适用于来自不同谱系和分化阶段的白血病细胞。更好地了解人类白细胞抗原II类抗原的处理和细胞内抗原递呈的机制，对于更好地开发以CD4+T细胞为基础的免疫治疗具有重要意义。

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.