In the context of HLA-DP-mismatched allogeneic stem cell transplantation, mismatched HLA-DP alleles can provoke profound allo-HLA-DP-specific immune responses from the donor T-cell repertoire leading to graft-versus-leukemia effect and/or graft-versus-host disease in the patient. The magnitude of allo-HLA-DP-specific immune responses has been shown to depend on the specific HLA-DP disparity between donor and patient and the immunogenicity of the mismatched HLA-DP allele(s). HLA-DP peptidome clustering (DPC) was developed to classify the HLA-DP molecules based on similarities and differences in their peptide-binding motifs. To investigate a possible categorization of HLA-DP molecules based on overlap of presented peptides, we identified and compared the peptidomes of the thirteen most frequently expressed HLA-DP molecules. Our categorization based on shared peptides was in line with the DPC classification. We found that the HLA-DP molecules within the previously defined groups DPC-1 or DPC-3 shared the largest numbers of presented peptides. However, the HLA-DP molecules in DPC-2 segregated into two subgroups based on the overlap in presented peptides. Besides overlap in presented peptides within the DPC groups, a substantial number of peptides was also found to be shared between HLA-DP molecules from different DPC groups, especially for groups DPC-1 and -2. The functional relevance of these findings was illustrated by demonstration of cross-reactivity of allo-HLA-DP-reactive T-cell clones not only against HLA-DP molecules within one DPC group, but also across different DPC groups. The promiscuity of peptides presented in various HLA-DP molecules and the cross-reactivity against different HLA-DP molecules demonstrate that these molecules cannot be strictly categorized in immunogenicity groups.

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Adoptive cellular therapies with T cells are increasingly used to treat a variety of conditions. For instance, in a recent phase I/II trial, we prophylactically administered multi-virus-specific T-cell products to protect recipients of T-cell depleted allogeneic stem-cell grafts against viral reactivations. To establish treatment efficacy, it is important to determine the fate of the individual transferred T-cell populations. However, it is difficult to unequivocally distinguish progeny of the transferred T-cell products from recipient- or stem-cell graft-derived T cells that survived T-cell depletion during conditioning or stem-cell graft manipulation. Using mRNA sequencing of the TCRβ-chains of the individual virus-specific T-cell populations within these T-cell products, we were now able to track the multiple clonal virus-specific subpopulations in peripheral blood and distinguish recipient- and stem-cell graft-derived virus-specific T cells from the progeny of the infused T-cell products. We observed in vivo expansion of virus-specific T cells that were exclusively derived from the T-cell products with similar kinetics as the expansion of virus-specific T cells that could also be detected before the T-cell product infusion. Additionally, we demonstrated persistence of virus-specific T cells derived from the T-cell products in most patients who did not show viral reactivations. This study demonstrates that virus-specific T cells from prophylactically infused multi-antigen-specific T-cell products can expand in response to antigen encounter in vivo and even persist in the absence of early viral reactivations.

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