Peptides Derived From Mismatched Paternal Human Leukocyte Antigen Predicted to Be Presented by HLA-DRB1, -DRB3/4/5, -DQ, and -DP Induce Child-Specific Antibodies in Pregnant Women.

Predicted Indirectly ReCognizable Human Leukocyte Antigen (HLA) Epitopes (PIRCHE) are known to be a significant risk factor for the development of donor HLA-specific antibodies after organ transplantation. Most previous studies on PIRCHE limited their analyses on the presentation of the HLA-DRB1 locus, although HLA-DRB3/4/5, -DQ, and -DP are also known for presenting allopeptides to CD4+ T cells. In this study, we analyzed the impact of predicted allopeptides presented by these additional loci on the incidence of HLA-specific antibodies after an immunization event. We considered pregnancy as a model system of an HLA immunization and observed child-specific HLA antibody (CSA) development of 231 mothers during pregnancy by samples being taken at delivery. Our data confirm that PIRCHE presented by HLA-DRB1 along with HLA-DRB3/4/5, -DQ, and -DP are significant predictors for the development of CSA. Although there was limited peptidome overlap observed within the mothers' presenting HLA proteins, combining multiple presenting loci in a single predictor improved the model only marginally. Prediction performance of PIRCHE further improved when normalizing scores by the respective presenters' binding promiscuity. Immunogenicity analysis of specific allopeptides could not identify significant drivers of an immune response in this small cohort, suggesting confirmatory studies.

Identification of Human Antigen-Specific CD4+ T-Cells with Peptide-MHC Multimer Technologies.

The development of peptide-MHC class II multimers has provided a novel approach in studying antigen-specific CD4+ T-cells and extended the knowledge of these T cells in various disease settings, including infectious diseases, autoimmune diseases, cancer, and allergies. This chapter discusses the various applications of the peptide-MHC class II multimer technologies, specifically their uses in the evaluation of antigen-specific CD4+ T-cells ex vivo, and their uses in epitope identification.

A naturally processed HLA-DR-bound peptide from the IL-9 receptor alpha of HTLV-1-transformed T cells serves as a T helper epitope.

Human T cell leukemia virus type 1 (HTLV-1) induced adult T cell leukemia/lymphoma (ATLL) is usually a fatal lymphoproliferative malignant disease. Thus, the enhancement of T cell immunity to ATLL through the development of therapeutic vaccines using characterized T cell peptide epitopes could be of value. We isolated and characterized HLA-DR-bound peptides from HTLV-1-transformed T cells by fractionating on reverse-phase high performance liquid chromatography and Edman NH(2)-terminal sequencing and were able to identify five independent peptide sequences. One of the identified peptide sequences corresponded to a fragment of the human interleukin-9 receptor alpha (IL-9Rα), which is commonly expressed by HTLV-1-infected T cell lymphoma cells. Using a synthetic peptide corresponding to the identified IL-9Rα sequence, we generated antigen-specific CD4 helper T lymphocytes in vitro, which were restricted by HLA-DR15 or HLA-DR53 molecules and could recognize and kill HTLV-1+, IL-9Rα+ T cell lymphoma cells. These results indicate that IL-9Rα functions as T cell leukemia/lymphoma-associated antigen for CD4 T cells and that synthetic peptides such as the one described here could be used for T cell-based immunotherapy against IL-9Rα positive ATLL.