Reassessing the role of HLA‐DRB3 T‐cell responses: Evidence for significant expression and complementary antigen presentation

Abstract

In humans, several HLA-DRB loci (DRB1/3/4/5) encode diverse b-chains that pair with a-chains to form DR molecules on the surface of APC. While DRB1 and DRB5 have been extensively studied, the role of DRB3/4 products of DR52/DR53 haplotypes has been largely neglected. To clarify the relative expression of DRB3, we quantified DRB3 mRNA levels in comparison with DRB1 mRNA from the same haplotype in both B cells and monocytes, observing quantitatively significant DRB3 synthesis. In CD19 1 cells, DRB1*03/11/13 was 3.5-fold more abundant than DRB3, but in CD14 1 this difference was only two-fold. Monocytes also had lower overall levels of DR mRNA compared with B cells, which was confirmed by cell surface staining of DRB1 and DRB3. To evaluate the functional role of DRB3, tetramerguided epitope mapping was used to detect T cells against tetanus toxin and several influenza antigens presented by DRB3*0101/0202 or DRB1*03/11/13. None of the epitopes discovered were shared among any of the DR molecules. Quantitative assessment of DRB3-tetanus toxin specific T cells revealed that they are present at similar frequencies as those observed for DRB1. These results suggest that DRB3 plays a significant role in antigen presentation with different epitopic preferences to DRB1. Therefore, DRB3, like DRB5, serves to extend and complement the peptide repertoire of DRB1 in antigen presentation. polymorphisms that influence the peptide binding properties of each variant. In addition to this diversity, certain DRB clusters contain a second ''duplicate'' DR b chain [3]. These duplications can be considered copy number polymorphisms, a re-discovered mechanism of gene variation [4]. In humans, next to DRB1, there are three functional secondary DRB chains: DRB3, DRB4 and DRB5. These secondary b chains can also combine with the common DRa chain to form additional DR molecules on the cell surface [5]. Although the polymorphisms in all DRB loci are analogous, DRB1 is clearly the most polymorphic with over 500 alleles described. The other DRB loci are less polymorphic: DRB3 has 45 alleles, DRB4 has 14 alleles and DRB5 has 18 alleles [6]. While DRB1 is present in all haplotypes, the secondary DRB loci are not found simultaneously in every individual. Rather, for any given HLA-DRB1 haplotype, only one secondary DRB gene such as DRB3, DRB4 or DRB5 may be present. This means that a maximum of four DRB products can be found in an individual. Furthermore, secondary DRB loci are in linkage disequilibrium with the DRB1, and therefore three main DRB haplotypes are defined: DR51, DR52 and DR53 [7]. These names originate from the serological classification of DR specificities created in the 1980s. The human HLA-DR52 haplotype comprises a single DRB1/DRB3 locus. However, several DRB1 alleles comprise this haplogroup: DRB1 Ã 03, DRB1 Ã 11, DRB1 Ã 12, DRB1 Ã 13, DRB1 Ã 14 (all of them named in this article HLA-DRB1-52). The role of DRB5 Ã 0101 in antigen presentation has been extensively studied due to the linkage disequilibrium with DRB1 Ã 15 and its associ...

Identification of a Wilms’ tumor 1-derived immunogenic CD4+ T-cell epitope that is recognized in the context of common Caucasian HLA-DR haplotypes

“…The observation of an additional binding capacity of WT1 332-347 to HLA-DRB3*02:02 further underscores its suitability for immunotherapeutic use, as this HLA class II molecule is highly prevalent among Caucasians (B50%) and appears to have an important role in (tumor) antigen presentation to CD4 þ T cells. 13,14 To conclude, this study confirms the potential broad applicability of WT1 332-347 -based immunotherapy clinical trials in Caucasian subjects with AML or other WT1-expressing tumor types. Such clinical studies may be highly warranted in view of the already established positive correlation between WT1 332-347 -directed immunity and clinical response in cancer patients.…”

GDP- l -fucose synthase is a CD4 + T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis

“…The HLA-DRB1*03 and the DRB3* haplotype most likely appeared via gene duplication of a common DRB1* gene in that locus, and in consequence, DRB3* has been considered a secondary redundant locus (50). However, the ability of DRB3* molecules to present a distinct pattern of peptides and the existence of DRB3*-restricted T cells in peripheral blood have been demonstrated (51). Here, we found that the GDP-l-fucose synthase peptide (51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65), the only peptide stimulatory in all high-responder DRB3*02:02 patients, showed the highest predicted binding affinity to this class II molecule, suggesting DRB3*02:02-restricted T cell recognition of this peptide.…”

Monitoring of NY-ESO-1 specific CD4 + T cells using molecularly defined MHC class II/His-tag-peptide tetramers

“…In particular, DR52b, encoded by one of the main DRB3 alleles, is expressed by half of Caucasians. In recent years, an increasing number of studies have concentrated on alternate DR molecules, describing their structure and binding characteristics and peptide binding motifs have been defined for several of them (13,26).…”