Identification of a novel UTY-encoded minor histocompatibility antigen.

Minor histocompatibility antigens (mHags) encoded by the Y-chromosome (H-Y-mHags) are known to play a pivotal role in allogeneic haematopoietic cell transplantation (HCT) involving female donors and male recipients. We present a new H-Y-mHag, YYNAFHWAI (UTY(139-147)), encoded by the UTY gene and presented by HLA-A*24:02. Briefly, short peptide stretches encompassing multiple putative H-Y-mHags were designed using a bioinformatics predictor of peptide-HLA binding, NetMHCpan. These peptides were used to screen for peptide-specific HLA-restricted T cell responses in peripheral blood mononuclear cells obtained post-HCT from male recipients of female donor grafts. In one of these recipients, a CD8+ T cell response was observed against a peptide stretch encoded by the UTY gene. Another bioinformatics tool, HLArestrictor, was used to identify the optimal peptide and HLA-restriction element. Using peptide/HLA tetramers, the specificity of the CD8+ T cell response was successfully validated as being HLA-A*24:02-restricted and directed against the male UTY(139-147) peptide. Functional analysis of these T cells demonstrated male UTY(139-147) peptide-specific cytokine secretion (IFNγ, TNFα and MIP-1ß) and cytotoxic degranulation (CD107a). In contrast, no responses were seen when the T cells were stimulated with patient tumour cells alone. CD8+ T cells specific for this new H-Y-mHag were found in three of five HLA-A*24:02-positive male recipients of female donor HCT grafts available for this study.

Extraordinary cross-reactivity of an autoimmune T-cell receptor recognizing specific peptides both on autologous and on allogeneic HLA class II molecules.

A T-cell receptor's (TCR) recognition of a human leukocyte antigen (HLA)-peptide complex (pHLA) is normally described as being restricted by the HLA molecule and specific for the peptide. This is, however, not always true. Several TCRs have been described, which cross-react with other peptides bound to the restricting HLA molecule. This phenomenon has been considered a variant of molecular mimicry and is suggested to be one of the mechanisms behind autoimmunity. The positive selection of T cells in the thymus imposes low-affinity recognition of the TCRs toward self-pHLA, which increases the probability of the TCR to be promiscuous by nature, and further implies that the T-cell repertoire contains TCRs prone to be autoreactive and thus able to induce autoimmunity. We present an autoimmune TCR showing extreme cross-reactivity to several pHLA comprising both own HLA class II restriction element and allogeneic HLA class II restriction elements in complex with both self-derived and microbially derived peptides. The existence of such a significant cross-reactivity in the context of distinct HLA-DR molecules might be more common among autoimmune TCRs than previously anticipated and potentially reveals a new way of designing altered peptide ligands for therapeutic use.