A surprising facet of allotransplantation is the intensity of host alloreactivity. A mature naïve T cell and its T-cell receptor (TCR) properly selected in the thymus react 100- to 1,000-fold more frequently with allogeneic major histocompatibility complex (MHC). The TCR recognition of allogeneic MHC is thought to be similar to peptide recognition by self-MHC; therefore, it is surprising given that these T cells are responding to MHC molecules that have not been encountered during thymic selection. Several models have been proposed to explain this phenomenon, including degenerate recognition of the MHC by the germline TCRs, peptides with multiple specificities, and differences in the flexibility in the docking angle. Importantly, this high alloreactivity has been a major barrier to organ and haplo-identical hematopoietic cell transplantation.
Since the early 1990s, several groups have described a small population of T cells (1 percent to 8 percent) in the periphery that carry two TCRs. These cells have a second TCRα chain that can pair with the TCRβ chain to form a functional TCR heterodimer. This second TCR can be found on the cell surface, through which signaling can occur and can contribute to immune responses.
In order to investigate the impact of this small population of T cells, Morris and Allen, from Washington University in St. Louis, tested whether the failure of allelic exclusion of the second TCRα chain could be responsible for the strong alloreactivity. They initially demonstrated in a mixed lymphocyte reaction that these dual TCR cells are found in the alloreactive cells. They used fluorescently labeled T cells from the B6 strain of mice stimulated non-specifically with anti-CD3 and anti-CD28 monoclonal antibodies (mAbs) or specifically with irradiated splenocytes from mouse strains mismatched at MHC loci (B6.K (H-2k) and BALB/c (H-2d), and responding T cells were stained with mAbs to detect specific TCR gene products. Non-specific stimulation did not change the frequency of the dual TCR cells, but exposure to allo-mismatched cells did. Moreover, they also showed at the single-cell level a dual TCR that is distinct in alloreactivity for each of the TCRs. Lastly, they demonstrated these changes in vivo in a model of graft-versus-host disease in which four weeks after transplant dual TCR T cells made up 6 percent to 75 percent of peripheral activated T cells! That these T cells have an activated phenotype suggests they are involved in the alloreactive responses.
In Brief
These observations are remarkable if confirmed. These small populations of T cells with dual TCRs have been described for many years and the biological function of these cells has not been well understood. The data would suggest that while single positive T cells can be alloreactive, these dual TCR T cells are disproportionately responsible for alloreactivity, given that in some animals up to 75 percent of the responding T cells had dual TCRs. It is important to note, however, that the distribution was quite varied from 6 percent to 75 percent from mouse to mouse, even though these are inbred mice. These data would also suggest that removal of these dual TCR T cells should result in less alloreactivity.
Competing Interests
Dr. Chao indicated no relevant conflicts of interest.
