Scanning for the origins of mHags

In this issue of Blood, Kamei and colleagues introduce an innovative approach for identifying the genes that encode novel T cell-defined human minor histocompatibility antigens (mHags). In this significant methodologic advance, they demonstrate how the rich human genetic variation data generated for the International Human HapMap Project, together with the available HapMap B-lymphoblastoid cell lines that have undergone extensive genome-wide sequencing, can be used to identify the functional genetic variants responsible for the cellular peptides recognized by selected T-cell clones.

Human minor histocompatibility antigens (mHags) have been recognized as barriers to successful hematopoietic cell transplantation (HCT) from normal donors for more than 30 years.¹  Success following HCT is ultimately determined by the ability to achieve sustained engraftment, eradication of abnormal or malignant host cells, and control of graft-versus-host disease (GVHD). Each of these clinical end points is influenced by the nature and extent of the genetic disparity between donor and recipient. Graft rejection and GVHD are immune-mediated reactions induced by histocompatibility differences between donor and recipient. GVHD occurs when immune-competent donor T cells are transplanted to an immune-compromised host, and the incompatibility between donor and recipient is sufficient to induce T-cell activation.²  The histocompatibility differences responsible for these T-cell responses are encoded by polymorphic genes located throughout the genome. T-cell recognition of these differences can occur only when the variant peptide in a recipient is foreign to the donor and is appropriately processed and presented at the cell surface by the HLA alleles of the recipient. Polymorphic peptides fulfilling these requirements are called mHags.^1,3 

Although severe GVHD has an adverse effect on morbidity and mortality, occurrence of GVHD is also associated with lower relapse rates, demonstrating that host reactivity of donor T cells can also mediate a significant graft-versus-leukemia (GVL) effect and thereby directly contributes to the curative potential of allogeneic HCT for patients with hematologic malignancy. The GVL effect has become an important model system for exploring new strategies aimed at improving the antitumor potential of T cell–based immunotherapy. These efforts have largely focused on understanding the mechanisms of GVL and the identification of the molecules that could be the potential targets for T-cell immunotherapy.^4,5  Improved techniques for cloning mHag-specific T cells and eluting candidate peptides from major histocompatibility complex molecules in the late 1980s made possible the initial identification of individual mHags. However, the process was difficult, and progress in expanding the library of well-characterized mHags has been slow.

In this issue of Blood, Kamei et al introduce a novel approach for identifying T cell–defined mHag loci using publically available resources generated by the International HapMap Project and including the B-lymphoblastoid cell lines that were the source of DNA sequenced for the HapMap project and the resulting large dataset of sequence-based genotypes.^6-8  These cell lines are publicly available, and once they have been transduced with the appropriate HLA restriction element, they can be tested as targets to determine whether they contain the DNA sequence necessary to encode specific T cell–defined peptides. Mapping of the gene encoding the mHag is accomplished by combining the results of immune-based functional assays with a whole genome association analysis by scanning the known sequence polymorphisms (SNPs) in the vast HapMap database, which currently consists of more than 3 million genetic markers expressed by these reference cell lines. The power and resolution of genetic mapping obtainable with this resource will continue to expand in the future as the numbers of new reference samples sequenced increases, and the racial diversity of the reference panel is broadened. The approach described here by Kamei et al should contribute substantially to the development of a more comprehensive and efficient characterization of mHags. This method may also prove useful for the genetic mapping of other genetic traits.