Functional Development of the T Cell Receptor for Antigen

Abstract

For over three decades now, the T cell receptor (TCR) for antigen has not ceased to challenge the imaginations of cellular and molecular immunologists alike. T cell antigen recognition transcends every aspect of adaptive immunity: it shapes the T cell repertoire in the thymus and directs T cell-mediated effector functions in the periphery, where it is also central to the induction of peripheral tolerance. Yet, despite its central position, there remain many questions unresolved: how can one TCR be specific for one particular peptide-major histocompatibility complex (pMHC) ligand while also binding other pMHC ligands with an immunologically relevant affinity? And how can a T cell’s extreme specificity (alterations of single methyl groups in their ligand can abrogate a response) and sensitivity (single agonist ligands on a cell surface are sufficient to trigger a measurable response) emerge from TCR–ligand interactions that are so low in affinity? Solving these questions is intimately tied to a fundamental understanding of molecular recognition dynamics within the many different contexts of various T cell–antigen presenting cell (APC) contacts: from the thymic APCs that shape the TCR repertoire and guide functional differentiation of developing T cells to the peripheral APCs that support homeostasis and provoke antigen responses in naïve, effector, memory, and regulatory T cells. Here, we discuss our recent findings relating to T cell antigen recognition and how this leads to the thymic development of foreign-antigen-responsive αβT cells.

Characterization of Distinct T Cell Receptor Repertoires in Tumor and Distant Non-tumor Tissues from Lung Cancer Patients

“…T cell responses to cancer cells depend largely on the affinity between T cell receptors (TCRs) and peptide-major histocompatibility complex (pMHC). Developing and maintaining highly diversified TCR repertoires to defend against numerous foreign pathogens is demanding [2]. TCRs are heterodimers composed of either specific α and β chains, representing the most common types of TCRs, or specific γ and δ chains.…”

Diversity index of mucosal resident T lymphocyte repertoire predicts clinical prognosis in gastric cancer

“…18 In response to the immense amount of foreign antigens, it is critical to develop and maintain a highly diversified TCR repertoire. 19 Ultimately, the diversity of TCR repertoire is generated by somatic recombination of the TCRA and TCRB loci during early development in the thymus. 20 During the rearrangement process, arrays of variable (V), diversity (D: only for the Beta chain of T-cell receptor) and joining (J) gene segments are reorganized and assembled by random and non-templated ligation to generate an antigen receptor.…”

Engineering approaches for regeneration of T lymphopoiesis

“…Lastly, there are concerted molecular mechanisms that allow developing T cells to migrate between regional compartments, one after another, which involves various chemokines and adhesion molecules. Excellent reviews that further detail the molecular interactions and developmental signaling events can be found elsewhere [ 8 , 9 ]. It should be noted that the cellular communications between developing T cells and thymic stroma are reciprocal, i.e.…”