The self-peptide repertoire plays a critical role in transplant tolerance induction

Abstract

While direct allorecognition underpins both solid organ allograft rejection and tolerance induction, the specific molecular targets of most directly-alloreactive CD8+ T cells have not been defined. In this study, we used a combination of genetically-engineered MHC I constructs, mice with a hepatocyte-specific mutation in the class I antigen-presentation pathway and immunopeptidomic analysis to provide definitive evidence for the contribution of the peptide cargo of allogeneic MHC I molecules to transplant tolerance induction. We established a systematic approach for the discovery of directly-recognised pMHC epitopes, and identified 17 strongly immunogenic H-2Kb-associated peptides recognised by CD8+ T cells from B10.BR (H-2k) mice, 13 of which were also recognised by BALB/c (H-2d) mice. As few as five different tetramers used together were able to identify almost 40% of alloreactive T cells within a polyclonal population. To our knowledge, this represents the first example of such an approach in the context of direct allorecognition.

The role of self-peptides in direct T cell allorecognition

“…Since TAP1 is essential for loading endogenous cytosolic peptides onto MHC I molecules (17), TAP1 deficiency vastly reduced and altered the self-peptide repertoire bound to the allogeneic MHC I molecule. Tolerance to allografts transplanted from TAP1-sufficient donors bearing the allogeneic MHC I molecule was completely abrogated (16). Together, the two approaches established that induction of allospecific tolerance to a non-self MHC I molecule in vivo is critically dependent ure 1C, yellow curve), or is it carried out by a sharp peak of immunodominant T cell clones akin to antiviral responses (Figure 1C, blue curve)?…”

“…In this issue of the JCI, Son et al used an elegant mouse transplantation tolerance model to provide compelling in vivo evidence for peptide dependence of direct allorecognition (16). In this model, adenoviral transduction of an allogeneic MHC I molecule into recipient hepatocytes rendered the mice tolerant to subsequent skin grafts bearing the same allogeneic MHC molecule.…”

“…The peptide-MHC tetramer panel was subsequently used to track alloreactive T cells in tolerized mice, demonstrating that the T cells had acquired an exhausted phenotype. Therefore, in addition to establishing a key role for self-peptides in direct alloreactivity, Son et al succeeded in putting the peptides to use by creating a tool that identifies a sizeable proportion of the alloreactive T cell repertoire in one fell swoop (16).…”

“…This maneuver induced tolerance in alloreactive T cells bearing the TCR specific to the defined single peptide but prevented tolerance in the polyclonal alloreactive T cell population. In the second approach, the authors transduced mice that lacked hepatocyte expression of the transporter associated with antigen processing 1 (TAP1) protein with an adenoviral vector encoding a stable form of the allogeneic MHC I molecule (16). Since TAP1 is essential for loading endogenous cytosolic peptides onto MHC I molecules (17), TAP1 deficiency vastly reduced and altered the self-peptide repertoire bound to the allogeneic MHC I molecule.…”

“…Manipulating peptide-MHC constructs should also open avenues for investigating whether altering the peptide cargo of MHC molecules can redirect the T cell response from rejection toward tolerance (19). Finally, researchers can apply approaches analogous to those of Son et al (16) to make accurate tracking of the human alloimmune response a clinical reality.…”