T‐Cell Antigen Recognition – Lessons from the Past and Projections into the Future

Abstract

T‐cells are central to adaptive immunity and arguably to this date the most intensely studied cells in life sciences. Paying tribute to their developmental plasticity and the complexities associated with many of their physiological functions, numerous aspects of their physiology are still far from being understood to an extent that would be sufficient to rationally design therapies effectively targeting allergies, autoimmunity and cancer. T‐cell antigen recognition is no exception: this field took up speed with the rise of monoclonal antibodies and the first successful cloning of the T‐cell antigen receptor (TCR) genes roughly 40 years ago. In the meantime, hundreds of TCRs have been crystallised in complex with their nominal peptide/MHC (pMHC) binding partners and many TCR‐pMHC interaction kinetics have been measured. Furthermore most, if not all signalling molecules acting downstream of the TCR have been identified. Despite these accomplishments, we are still searching for convincing explanations as to how T‐cells mange to reliably detect the presence of even a single antigen on the surface of antigen‐presenting cells (APCs). Elaborating underlying mechanisms will invariably require a more advanced understanding of the molecular, subcellular and cellular context in which T‐cell antigen recognition operates. What renders this endeavour both challenging and exciting is the rather weak strength and promiscuous nature of TCR‐pMHC binding and the fact that antigenic pMHCs are typically vastly outnumbered on APC surfaces by structurally similar, yet nonstimulatory pMHCs. While research of the last 20 years has provided some clarity, it has also caused at times controversies, which need to be resolved to unleash the full potential that T‐cells offer for clinical progress. Key Concepts T‐cells are indispensable for orchestrating and executing cellular and humoral adaptive immune responses; in recurrent communication with other cells of the immune system, T‐cells continuously patrol our body in search for antigenic peptide fragments derived from pathogens or cancer‐derived neoantigens. T‐cells are exquisitely sensitive for their nominal antigen as they can detect the presence of even a single stimulatory pMHC amongst thousands of structurally similar yet nonstimulatory pMHCs on the very crowded surface of an APC. Despite considerable progress in the field over the last 40 years, the molecular, biophysical and (sub‐) cellular principles underlying the detection efficiency associated with T‐cell antigen recognition and are far from being resolved. Given the complexities inherent to processes associated with T‐cell antigen recognition, which involve (1) the short‐lived nature of key protein–protein and protein–lipid interactions and (2) mechanical forces acting within the narrow confines of the immunological synapse, we consider integrative approaches combining classical biochemistry, structural biology and genetics with biophysics, advanced live‐cell imaging and systems biology most likely to provide much‐needed answers to most fundamental questions. Easy access to both experimental/analysis modalities and primary data of published work as well as improved literacy in the areas of biophysics and systems biology will help accelerate progress in the field of T‐cell antigen recognition with immediate and far‐reaching clinical implications benefiting allergy, autoimmune and cancer patients.

Aggregation‐prone peptides from within a non‐self‐protein homoaggregate are preferred for MHC association: Historical overview

“…3 Indeed, Platzer and Huppa recognize that through thymic positive selection 'high-affinity TCRs emerging in the periphery are rare as they are probably sorted out during based residual affinities towards self-MHCs'. 3 Yet, there remains puzzlement as to 'why some thymocytes expressing self-reactive TCRs get a pass during negative selection only to later destroy healthy tissue in the periphery as mature T-cells'. 3 The present broad overview hopes to reduce this puzzlement.…”

“…3 Yet, there remains puzzlement as to 'why some thymocytes expressing self-reactive TCRs get a pass during negative selection only to later destroy healthy tissue in the periphery as mature T-cells'. 3 The present broad overview hopes to reduce this puzzlement.…”

“…As novel technologies begin to change the perspective of those long involved in the field, 18 there is increasing recognition that: ‘Achieving deep knowledge of the decisive factors driving T‐cell antigen recognition will likely require an integrative approach, which is no more limited to methodological disciplines of the twentieth century’ 3 . Indeed, Platzer and Huppa recognize that through thymic positive selection ‘high‐affinity TCRs emerging in the periphery are rare as they are probably sorted out during based residual affinities towards self‐MHCs’ 3 . Yet, there remains puzzlement as to ‘why some thymocytes expressing self‐reactive TCRs get a pass during negative selection only to later destroy healthy tissue in the periphery as mature T‐cells’ 3 .…”

“…1 Many studies have focused on amino acid interactions between specific T cell receptors (TCRs) and the corresponding pMHCs, with less consideration of other factors. [2][3][4] Yet it has long been known that some peptides are capable of 'self-assembling' (i.e. forming nanofiber or nanoparticle homoaggregates), a process that seems to confer immune-enhancing (adjuvant) properties.…”

“…Many studies have focused on amino acid interactions between specific T cell receptors (TCRs) and the corresponding pMHCs, with less consideration of other factors 2–4 . Yet it has long been known that some peptides are capable of ‘self‐assembling’ (i.e.…”