Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity.

The inherent cross-reactivity of the T cell receptor (TCR) is balanced by high specificity, which often manifests in confounding ways not easily interpretable from static structures. We show here that TCR discrimination between an HLA-A*03:01 (HLA-A3)-restricted public neoantigen derived from mutant and its wild-type (WT) counterpart emerges from motions within the HLA binding groove that vary with the identity of the peptide's first primary anchor. The motions form a dynamic gate that in the complex with the WT peptide impedes a large conformational change required for TCR binding.

Enhanced T cell receptor specificity through framework engineering.

Development of T cell receptors (TCRs) as immunotherapeutics is hindered by inherent TCR cross-reactivity. Engineering more specific TCRs has proven challenging, as unlike antibodies, improving TCR affinity does not usually improve specificity. Although various protein design approaches have been explored to surmount this, mutations in TCR binding interfaces risk broadening specificity or introducing new reactivities.

Structural and physical features that distinguish tumor-controlling from inactive cancer neoepitopes.

Neoepitopes arising from amino acid substitutions due to single nucleotide polymorphisms are targets of T cell immune responses to cancer and are of significant interest in the development of cancer vaccines. However, understanding the characteristics of rare protective neoepitopes that truly control tumor growth has been a challenge, due to their scarcity as well as the challenge of verifying true, neoepitope-dependent tumor control in humans. Taking advantage of recent work in mouse models that circumvented these challenges, here, we compared the structural and physical properties of neoepitopes that range from fully protective to immunologically inactive.

The Energetic Landscape of Catch Bonds in TCR Interfaces.

Recognition of peptide/MHC complexes by αβ TCRs has traditionally been viewed through the lens of conventional receptor-ligand theory. Recent work, however, has shown that TCR recognition and T cell signaling can be profoundly influenced and tuned by mechanical forces. One outcome of applied force is the catch bond, where TCR dissociation rates decrease (half-lives increase) when limited force is applied.

Peptide-dependent tuning of major histocompatibility complex motional properties and the consequences for cellular immunity.

T cell receptors (TCRs) and other receptors of the immune system recognize peptides presented by class I or class II major histocompatibility complex (MHC) proteins. Although we generally distinguish between the MHC protein and its peptide, at an atomic level the two form a structural composite, which allows peptides to influence MHC properties and vice versa. One consequence is the peptide-dependent tuning of MHC structural dynamics, which contributes to protein structural adaptability and influences how receptors identify and bind targets.

Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner.

Presentation of peptides by class I MHC proteins underlies T cell immune responses to pathogens and cancer. The association between peptide binding affinity and immunogenicity has led to the engineering of modified peptides with improved MHC binding, with the hope that these peptides would be useful for eliciting cross-reactive immune responses directed toward their weak binding, unmodified counterparts. Increasing evidence, however, indicates that T cell receptors (TCRs) can perceive such anchor-modified peptides differently than wild-type (WT) peptides, although the scope of discrimination is unclear.

Structural dissimilarity from self drives neoepitope escape from immune tolerance.

T-cell recognition of peptides incorporating nonsynonymous mutations, or neoepitopes, is a cornerstone of tumor immunity and forms the basis of new immunotherapy approaches including personalized cancer vaccines. Yet as they are derived from self-peptides, the means through which immunogenic neoepitopes overcome immune self-tolerance are often unclear. Here we show that a point mutation in a non-major histocompatibility complex anchor position induces structural and dynamic changes in an immunologically active ovarian cancer neoepitope.

Geometrical characterization of T cell receptor binding modes reveals class-specific binding to maximize access to antigen.

Recognition of antigenic peptides bound to major histocompatibility complex (MHC) proteins by αβ T cell receptors (TCRs) is a hallmark of T cell mediated immunity. Recent data suggest that variations in TCR binding geometry may influence T cell signaling, which could help explain outliers in relationships between physical parameters such as TCR-pMHC binding affinity and T cell function. Traditionally, TCR binding geometry has been described with simple descriptors such as the crossing angle, which quantifies what has become known as the TCR's diagonal binding mode.

Dynamically Driven Allostery in MHC Proteins: Peptide-Dependent Tuning of Class I MHC Global Flexibility.

T cell receptor (TCR) recognition of antigenic peptides bound and presented by class I major histocompatibility complex (MHC) proteins underlies the cytotoxic immune response to diseased cells. Crystallographic structures of TCR-peptide/MHC complexes have demonstrated how TCRs simultaneously interact with both the peptide and the MHC protein. However, it is increasingly recognized that, beyond serving as a static platform for peptide presentation, the physical properties of class I MHC proteins are tuned by different peptides in ways that are not always structurally visible.

Improving T Cell Receptor On-Target Specificity via Structure-Guided Design.

T cell receptors (TCRs) have emerged as a new class of immunological therapeutics. However, though antigen specificity is a hallmark of adaptive immunity, TCRs themselves do not possess the high specificity of monoclonal antibodies. Although a necessary function of T cell biology, the resulting cross-reactivity presents a significant challenge for TCR-based therapeutic development, as it creates the potential for off-target recognition and immune toxicity.

Peptide and Peptide-Dependent Motions in MHC Proteins: Immunological Implications and Biophysical Underpinnings.

Structural biology of peptides presented by class I and class II MHC proteins has transformed immunology, impacting our understanding of fundamental immune mechanisms and allowing researchers to rationalize immunogenicity and design novel vaccines. However, proteins are not static structures as often inferred from crystallographic structures. Their components move and breathe individually and collectively over a range of timescales.

Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition.

In cellular immunity, T cells recognize peptide antigens bound and presented by major histocompatibility complex (MHC) proteins. The motions of peptides bound to MHC proteins play a significant role in determining immunogenicity. However, existing approaches for investigating peptide/MHC motional dynamics are challenging or of low throughput, hindering the development of algorithms for predicting immunogenicity from large databases, such as those of tumor or genetically unstable viral genomes.

A generalized framework for computational design and mutational scanning of T-cell receptor binding interfaces.

T-cell receptors (TCRs) have emerged as a new class of therapeutics, most prominently for cancer where they are the key components of new cellular therapies as well as soluble biologics. Many studies have generated high affinity TCRs in order to enhance sensitivity. Recent outcomes, however, have suggested that fine manipulation of TCR binding, with an emphasis on specificity may be more valuable than large affinity increments.

Differential utilization of binding loop flexibility in T cell receptor ligand selection and cross-reactivity.

Complementarity determining region (CDR) loop flexibility has been suggested to play an important role in the selection and binding of ligands by T cell receptors (TCRs) of the cellular immune system. However, questions remain regarding the role of loop motion in TCR binding, and crystallographic structures have raised questions about the extent to which generalizations can be made. Here we studied the flexibility of two structurally well characterized αβ TCRs, A6 and DMF5.

Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity.

The mutational repertoire of cancers creates the neoepitopes that make cancers immunogenic. Here, we introduce two novel tools that identify, with relatively high accuracy, the small proportion of neoepitopes (among the hundreds of potential neoepitopes) that protect the host through an antitumor T cell response. The two tools consist of (a) the numerical difference in NetMHC scores between the mutated sequences and their unmutated counterparts, termed the differential agretopic index, and (b) the conformational stability of the MHC I-peptide interaction.

Peptide modulation of class I major histocompatibility complex protein molecular flexibility and the implications for immune recognition.

T cells use the αβ T cell receptor (TCR) to recognize antigenic peptides presented by class I major histocompatibility complex proteins (pMHCs) on the surfaces of antigen-presenting cells. Flexibility in both TCRs and peptides plays an important role in antigen recognition and discrimination. Less clear is the role of flexibility in the MHC protein; although recent observations have indicated that mobility in the MHC can impact TCR recognition in a peptide-dependent fashion, the extent of this behavior is unknown.