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

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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.