Understanding the Molecular Basis for an Alloreactive T-Cell Receptor to Achieve Peptide and MHC Specificity

The adaptive immune system provides a highly specialized pathway, which can recognize and protect against pathogens. The cell-mediated immune response is a component of the adaptive immune system which responds to infected or aberrant cells. T-cell receptors (TCRs) are heterodimeric molecules expressed on the surface of T lymphocytes. Their function is to recognize peptide antigens presented on major histocompatibility complex (MHC) proteins, which are expressed on the surface of antigen presenting cells (APCs). The repertoire of TCRs is the result of the thymic education process during, which precursor T cells undergo both positive and negative selection to acquire tolerance of self-peptides presented on self-MHC molecule [1]. However, TCRs are capable of responding to foreign or non-self MHC proteins in a well-established phenomenon termed alloreactivity, as evidenced by the rejection of transplanted organs and graft-versus-host disease (GVHD).

T-cell receptor (TCR) allorecognition is often believed to proceed with limited specificity, owing to either a TCR focus on the exposed polymorphic residues on the non-self MHC (MHC-centric) or the degenerate recognition of allopeptides (peptide-centric) [2]. For instance, the precursor frequency for alloreactive T cells is 100-fold to 1000-fold higher than that of convention T cells that are specific for one foreign-peptide-self MHC complex [3]. The large difference in precursor frequency suggested nonspecific allorecognition. Surprisingly however, alloreactive T cells can achieve high peptide and MHC specificity [4]. Although the underlying molecular mechanisms remain elusive, people are interested in the use of such highly specific alloreactive TCRs in cancer immunotherapy. In this dissertation, we mainly discuss how an alloreactive TCR achieves both peptide and MHC specificity. In contrast with current theories of alloreactivity (MHC-centric or peptide-centric), our structural and biophysical data suggests that high specific allorecognition is critically depend on the unique features of allogeneic MHC and the antigen peptide, relatively. More importantly, our findings emphasize that the peptide features working together with the distinctive surface chemistry of allogeneic MHC, can direct the specificity of allorecognition. Our results broaden the understanding of the specificity of allorecognition and provide insight into the use of allospecific TCRs in immunotherapy.