HLA最新文献

The anti-tumour immune response plays a pivotal role in eliminating tumour cells, with the presence of tumour-infiltrating lymphocytes (TILs) often correlated with improved patient outcomes. Among these, CD4+ T lymphocytes act as key orchestrators of the immune response, functioning as effector and regulatory cells, and are essential for establishing immunological memory. To better understand the role of CD4+ T cells in anti-tumour immunity, we analysed the HLA-II immunopeptidome of dendritic cells (DCs) from HLA-heterozygous donors pulsed with a protein extract from the MCF-7 tumour cell line. Our objective was to identify differences in the arrays of peptides binding distinct HLA-DRB1 allele combinations and the effect of DC pulsing on peptide presentation. We found that presented peptide repertoires are strongly influenced by HLA-DR heterozygosity in an allele-specific manner. Alleles with high binding strength (e.g., DRB1*01:01, DRB1*03:01 and DRB1*04:04) tended to dominate peptide presentation; however, this dominance is significantly modulated by the allelic combination, suggesting that antigen presentation is shaped not only by individual allele properties but also by their combinations. Pulsing DCs with MCF-7 extracts increased peptide overlap between donors and enabled the identification of 58 proteins putatively derived from the tumour cell line lysates. Interestingly, peptide presentation from these proteins reinforced allele-specific features of dominance and weakness previously observed across the entire immunopeptidome. Gaining insights into the peptide repertoire presented by distinct HLA-DR combinations could inform the design of personalised immunotherapies based on peptide-pulsed DCs, ultimately enhancing CD4+ TIL responses across diverse patient populations.

Bovine leukaemia virus (BLV) infects cattle, integrates into the host genome as a provirus, and induces a persistent infection that remains asymptomatic but can cause leukaemia/lymphoma. Most BLV-infected cell clones are created by massive depletion, and a few of these infected cell clones expand through the mitotic cycle, leading to the onset of lymphoma. Bovine lymphocyte antigen (BoLA)-DRB3 polymorphism is associated with susceptibility to BLV-induced leukemogenesis. However, whether BoLA-DRB3 polymorphism affects the clonality of BLV-infected cells in vivo remains unknown. Here, we investigated whether lymphoma integration sites have specific features in cattle with varying susceptibility to lymphoma. Genomic DNA was extracted from 99 BLV-infected Holstein cattle with lymphoma in a nationwide survey across Japan, and the integration sites were analysed using BLV proviral DNA-capture sequencing, which we had previously developed. Among the integration sites identified in 99 animals, no identical sites were confirmed. Comparison of integration sites between cattle with susceptible and resistant BoLA-DRB3 alleles showed no significant differences in the distribution of integration sites on the chromosome and in the genes and intergenic regions. With respect to the orientation of the proviruses, or proviral structures between individuals with resistance or susceptibility to lymphoma. In contrast, resistant animals showed a significantly higher proportion of monoclonal cell types than susceptible animals. In summary, the BoLA-DRB3 polymorphism affects BLV clonality; for example, there is massive depletion and clonal expansion of infected cell clones in fully transformed clones obtained from BLV-infected cattle with lymphoma.

The interaction between T-cell receptors (TCRs) and antigenic peptides presented by HLA molecules is fundamental to adaptive immunity. However, the extreme polymorphism of HLA genes poses major challenges for transplantation, antigen discovery, immunotherapy and studies of allele-specific function. Although CRISPR/Cas9 has transformed gene editing, existing sgRNA design tools are not optimised for knockout of HLA Class I genes due to their high rates of polymorphism. To address this, we developed HLA-Knockout (https://hlaknockout.rutgers.edu), a novel web-based tool that enables precise, allele-specific targeting of HLA Class I genes. HLA-Knockout retrieves user-defined HLA sequences from the IPD-IMGT/HLA database and applies stringent design criteria, including mismatch filtering and PAM disruption analysis, to ensure high specificity and minimal off-target effects on non-target HLA Class I alleles. Using HLA-Knockout, we achieved efficient single- and double-allele HLA Class I knockouts in human cells without disrupting non-target HLA Class I alleles. Functional assays confirmed allele-specific loss of antigen-specific TCR activation, validating the platform's utility. HLA-Knockout provides a unique resource for dissecting HLA-restricted immune interactions and has broad applications in transplantation biology, autoimmunity and cancer immunotherapy.