Minor histocompatibility antigens (mHAgs) are formed by polymorphic peptides located in the helical grooves of the major histocompatibility complex (MHC) molecules. These mHAgs are recognized by T-lymphocyte clones and provoke T-cell immune responses, thus playing an important clinical role in mediating both the graft-versus-host disease and graft-versus-leukemia effects of allogeneic hematopoietic stem cell transplantation. Although they can be expressed ubiquitously on tissues throughout the body, several recently discovered mHAgs are expressed selectively on hematopoietic cells. Until now, all of these hematopoietic-specific mHAgs have been identified on MHC class I molecules, with recognition by CD8+ T cells. However, Spaapen and colleagues have discovered the first hematopoietic-restricted mHAg on an MHC class II molecule, with recognition by CD4+ T cells, a discovery that offers tremendous opportunity for developing selective cytotoxic responses in cancer immunotherapy.
The identification of mHAg peptides and the genes encoding them is an important step in deciphering the role of individual mHAgs and their specific T-cell clones. However, discovering these genes has traditionally been a laborious and time-consuming process. Spaapen, et al. have not only identified an important minor H antigen, but they have also discovered a powerful new genetic tool for identifying genes encoding mHAgs. The authors first isolated a specific mHAg clone from a multiple myeloma patient and performed a genome-wide, two-point linkage analysis to identify a large region of interest on chromosome 16. Then, using a novel genetic strategy termed “zygosity-genotype correlation analysis,” they were able to correlate the zygosity of a given individual with previously identified SNP genotypes on chromosome 16, which allowed them to precisely map the genetic locus of this antigen to a single nucleotide substitution within the third exon of CD19. Further testing, including reactivity with CD19-specific T-cell clones, confirmed that this class II mHAg is encoded by the CD19 allele.
CD19 is a cell surface receptor that is expressed on normal lymphocytes from the earliest stages of pre-B-cell development through terminal differentiation into plasma cells, as well as on B-cell malignancies. Because this class II mHAg is not present on myeloid lineage cells or pluripotent stem cells, it presents an attractive potential target for directing an mHAg-specific T-cell clone against B-cell malignancies. And functional testing did reveal that these mHAg-specific CD4+ T cells demonstrated anti-tumor effects by directly lysing CD19-positive tumor cells in vitro.
In Brief
Minor histocompatibility antigens are important potential targets for future immunotherapeutic treatments, and the identification of the polymorphic genes encoding mHAgs is an important step in directing the anti-tumor activity of mHAg-specific T-cell clones. Applying their zygosity-genotype correlation analysis using the complete genome-wide set of HapMap SNPs, the authors were able to precisely map the genetic locus of a wide range of previously identified mHAg clones using the data from only 23 individuals, showing the broad clinical applicability of this novel genetic strategy. The discovery of hematopoietic lineage-restricted responses within the T-cell receptor and the ability to precisely and easily locate the genetic locus of these mHAgs should provide new opportunities to manipulate these responses in a wide range of hematologic diseases.
Competing Interests
Drs. Gilbert and Prchal indicated no relevant conflicts of interest.
