ROTRF Recognition Prize – Recognising Excellence in Organ Transplantation Research

12:10: A Molecular Basis for T Cell-mediated Alloreactivity

Jamie Rossjohn, Monash University, Clayton, Australia

Central to the adaptive immune response is the interaction between a T cell receptor (TCR) and peptide-loaded major histocompatibility complex molecules (pMHC). This is a complicated interaction because the TCR co-recognizes peptide antigen and MHC. Therefore, TCR specificity must accommodate the highly polymorphic nature of the MHC, an important feature that enables the MHC molecule to bind to an enormously variable set of microbial antigens. This leads to a vast T cell repertoire of clonally distributed TCRs in order to cope with this pMHC variability. Despite this receptor-ligand diversity, T cell responses are genetically restricted to recognizing host MHC molecules (MHC-restriction) while simultaneously retaining antigen specificity.

During thymic T cell development, TCRs destined to be useful to the host are selected for weak reactivity with one or more self-peptides in complex with self-MHC; subsequently these TCRs can potentially crossreact with microbial peptides complexed to self-MHC. TCR crossreactivity is an important feature of our immune system but can be a double-edged sword as the rule of MHC-restriction is violated when T cells are exposed to foreign (allogeneic) pMHC complexes. In the case of organ transplantation, up to 10% of naive T cells react strongly to allogeneic pMHC leading to allograft rejection and graft-versus-host disease. My presentation will focus on the molecular bases of T cell-mediated alloreactivity, and specifically how molecular mimicry can underpin human T cell alloreactivity.

Jamie Rossjohn

Prof. Jamie Rossjohn’s primary contributions span seminal discoveries in the pathogenesis of infectious human diseases, adaptive and innate immunity and autoimmunity. Regarding infection, his research has unraveled the molecular mechanism of two toxin families - the cholesterol-dependent cytolysins and the AB5 toxins. Regarding immunity, Prof. Rossjohn has provided a fundamental understanding in the MHC-restricted immune response and T-cell alloreactivity and how NKT T cell receptor-mediated lipid antigen recognition differs markedly from that of peptide recognition, as well as providing fundamental insight into the central role of the pre-TCR in T cell development. Prof. Rossjohn has published over 180 papers in peer-reviewed journals, including numerous publications in Nature, Cell, Science, PNAS, Nature Immunology, Immunity and Journal of Experimental Medicine.