Identification of novel HLA class II target epitopes for generation of donor-specific T regulatory cells

Therapies capable of generating host T regulatory cells (TR) responsive to donor-specific HLA-class II minor histocompatibility antigens have the potential to promote tolerance of a transplanted organ. Our group has developed a novel approach for the identification of potentially therapeutic TR target antigens. We perform parallel non-synonymous SNP genotyping of HLA-identical subject pairs to identify peptide variations expressed by only one of the two subjects. Variant peptide pairs are then evaluated for binding a shared HLA-class II allele. Minor peptides predicted to bind HLA-class II with greater affinity than the common variant peptide are tested for HLA class II binding and in vitro induction of suppressive CD4+ T cells. Using this approach we have identified multiple pairs of variant peptides capable of differential binding and induction of suppressive CD4+ T cells. These data demonstrate the feasibility of identifying potentially therapeutic HLA class II minor antigens for generation of donor-specific TR.

► Exome sequencing ~ 4000 to 6000 protein level disparities in unrelated transplants. ► Epitope prediction and peptide binding studies identified 3 novel minor epitopes. ► Two novel minor epitopes were capable of inducing suppressive CD4+ T cells in-vitro. ► Generation of donor specific T regulatory cells is feasible.