Exploiting T cells specific for human minor histocompatibility antigens for therapy of leukemia

Abstract

Minor histocompatibility (H) antigens are major targets of a graft-versus-leukemia (GVL) effect mediated by donor CD8(+) and CD4(+) T cells following allogeneic hematopoietic cell transplantation (HCT) between human leukocyte antigen identical individuals. In the 15 years since the first molecular characterization of human minor H antigens, significant strides in minor H antigen discovery have been made as a consequence of advances in cellular, genetic and molecular techniques. Much has been learned about the mechanisms of minor H antigen immunogenicity, their expression on normal and malignant cells, and their role in GVL responses. T cells specific for minor H antigens expressed on leukemic cells, including leukemic stem cells, can be isolated and expanded in vitro and infused into allogeneic HCT recipients to augment the GVL effect to prevent and treat relapse. The first report of the adoptive transfer of minor H antigen-specific T-cell clones to patients with leukemic relapse in 2010 illustrates the potential for the manipulation of alloreactivity for therapeutic benefit. This review describes the recent developments in T-cell recognition of human minor H antigens, and efforts to translate these discoveries to reduce leukemia relapse after allogeneic HCT.

Figure 1

The cartoon illustrates the pathways of generation and presentation of minor H antigens, and the recognition of minor H antigens by donor T cells during allogeneic HCT. Minor H antigens arise as a consequence of the normal cellular mechanisms for processing and presenting foreign antigens to T cells. Polymorphic genes are transcribed and translated and short peptide sequences are generated by proteolytic digestion of longer precursors in the proteosome. The peptides are transported into the endoplasmic reticulum by the peptide transporter (TAP) and loaded onto MHC class I molecules. The peptide-MHC complex is subsequently presented on the cell surface. In the setting of allogeneic HCT, polymorphisms in the recipient genome can result in the expression of proteins and peptides that are distinct from those in donor cells. Donor T cells fail to recognize self-peptides presented on the cell surface of donor cells due to thymic and peripheral tolerance mechanisms. However, there are high avidity T cells in the donor repertoire that can recognize recipient minor H antigens and these cells become activated following allogenic HCT and contribute to GVHD and to the GVL effect.

Figure 2

The figure depicts the accelerating pace of minor H antigen discovery. Each year in which a molecularly characterized autosomal chromosome-associated human minor H antigen was discovered is marked on the horizontal time line by the vertical arrows. The name(s) of one or more minor H antigen identified in each discovery year is listed above the corresponding arrows.