A Single Nucleotide Polymorphism in CD19 Defines a Novel Target for Immunotherapy of B Cell Malignancies with CD4⁺ Cytotoxic T Cells.

The Graft-versus-Tumor (GvT) effect of HLA-matched allogeneic stem cell transplantation (allo-SCT) is largely mediated by donor-derived alloreactive CD4⁺ and CD8⁺ T cells. Major targets of this curative effect are the minor Histocompatibility antigens (mHags) expressed on the malignant cells. Here we report the first mHag encoded by a hematopoietic gene and recognized by HLA class II (HLA-DQA1*05/B1*02)-restricted CD4⁺ T cells. This antigen is encoded by a single nucleotide polymorphism (SNP) in the B cell lineage-specific CD19 gene, a highly important target antigen for immunotherapy of almost all B cell malignancies. We identified this antigen using a novel and powerful genetic strategy, in which a phenotype-genotype correlation scanning was the key step for fine-mapping the genetic locus defined by pair-wise linkage analysis. In functional assays, CD4⁺ T cells specific for the CD19^L-encoded mHag mediated effective peptide-dependent maturation of DCs and polarized them to produce significant levels of interleukin-12. In another assay, the CD19^L-mHag-specific T cells facilitated the proliferation of a CD8⁺ mHag-specific T cell clone in an antigen-dependent manner. Even more important, they also lysed CD19^L-positive malignant cells, illustrating the therapeutic advantages of targeting this CD19 ^L -derived, HLA class II-restricted mHag. The currently available immunotherapy strategies enable the exploitation of these therapeutic effects within and beyond allo-SCT settings.