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Articles 61 - 67 of 67
Full-Text Articles in Medical Nutrition
Single-Chain Vαvβ T Cell Receptors Function Without Mispairing With Endogenous Tcr Chains1, David H. Aggen, Adam S. Chervin, Thomas M. Schmitt, Boris Engels, Jennifer D. Stone, Sarah A. Richman, Kurt H. Piepenbrink, Brian M. Baker, Philip D. Greenberg, Hans Schreiber, David M. Kranz
Single-Chain Vαvβ T Cell Receptors Function Without Mispairing With Endogenous Tcr Chains1, David H. Aggen, Adam S. Chervin, Thomas M. Schmitt, Boris Engels, Jennifer D. Stone, Sarah A. Richman, Kurt H. Piepenbrink, Brian M. Baker, Philip D. Greenberg, Hans Schreiber, David M. Kranz
Food for Health: Publications
Transduction of exogenous T cell receptor (TCR) genes into patients’ activated peripheral blood T cells is a potent strategy to generate large numbers of specific T cells for adoptive therapy of cancer and viral diseases. However, the remarkable clinical promise of this powerful approach is still being overshadowed by a serious potential consequence: mispairing of the exogenous TCR chains with endogenous TCR chains. These “mixed” heterodimers can generate new specificities that result in graft-versus-host reactions. Engineering TCR constant regions of the exogenous chains with a cysteine promotes proper pairing and reduces the mispairing, but, as we show here, does not …
Conformational Melding Permits A Conserved Binding Geometry In Tcr Recognition Of Foreign And Self Molecular Mimics, Oleg Y. Borbulevych, Kurt H. Piepenbrink, Brian M. Baker
Conformational Melding Permits A Conserved Binding Geometry In Tcr Recognition Of Foreign And Self Molecular Mimics, Oleg Y. Borbulevych, Kurt H. Piepenbrink, Brian M. Baker
Food for Health: Publications
Molecular mimicry between foreign and self antigens is a mechanism of T cell receptor cross reactivity and is thought to contribute to the development of autoimmunity. The αβ TCR A6 recognizes the foreign antigen Tax from the virus HTLV-1 when presented by the class I MHC HLA-A2. In a possible link with the autoimmune disease HAM/TSP, A6 also recognizes a self peptide from the neuronal protein HuD in the context of HLA-A2. We found here that the complexes of the HuD and Tax epitopes with HLA-A2 are close but imperfect structural mimics, and that in contrast with other recent structures …
Disparate Degrees Of Hypervariable Loop Flexibility Control T Cell Receptor Cross-Reactivity, Specificity, And Binding Mechanism, Daniel R. Scott, Oleg Y. Borbulevych, Kurt H. Piepenbrink, Steven A. Corcelli, Brian M. Baker
Disparate Degrees Of Hypervariable Loop Flexibility Control T Cell Receptor Cross-Reactivity, Specificity, And Binding Mechanism, Daniel R. Scott, Oleg Y. Borbulevych, Kurt H. Piepenbrink, Steven A. Corcelli, Brian M. Baker
Food for Health: Publications
αβ T cell receptors recognize multiple antigenic peptides bound and presented by major histocompatibility complex molecules. TCR cross-reactivity has been attributed in part to flexibility of the complementarity-determining region loops, yet there have been limited direct studies of loop dynamics to determine the extent of its role. Here we studied the flexibility of the binding loops of the αβ TCR A6 utilizing crystallographic, spectroscopic, and computational methods. A significant role for flexibility in binding and cross-reactivity was indicated only for the CDR3α and CDR3β hypervariable loops. Examination of the energy landscapes of these two loops indicated that CDR3β possesses a …
Identification And Engineering Of Human Variable Regions That Allow Expression Of Stable Single-Chain T Cell Receptors, David H. Aggen, Adam S. Chervin, Francis K. Insaidoo, Kurt H. Piepenbrink, Brian M. Baker, David M. Kranz
Identification And Engineering Of Human Variable Regions That Allow Expression Of Stable Single-Chain T Cell Receptors, David H. Aggen, Adam S. Chervin, Francis K. Insaidoo, Kurt H. Piepenbrink, Brian M. Baker, David M. Kranz
Food for Health: Publications
Single-chain antibody fragments (scFv), consisting of two linked variable regions (VH and VL), are a versatile format for engineering and as potential antigen-specific therapeutics. Although the analogous format for T cell receptors (TCRs), consisting of two linked V regions (Vα and Vβ; referred to here as scTv), could provide similar opportunities, all wild-type scTv proteins examined to date are unstable. This obstacle has prevented scTv fragments from being widely used for engineering or therapeutics. To further explore whether some stable human scTv fragments could be expressed, we used a yeast system in which display of properly folded …
Fluorine Substitutions In An Antigenic Peptide Selectively Modulate T Cell Receptor Binding In A Minimally Perturbing Manner, Kurt H. Piepenbrink, Oleg Y. Borbulevych, Ruth F. Sommese, John Clemens, Kathrynq M. Armstrong, Clare Desmond, Priscilla Do, Brian M. Baker
Fluorine Substitutions In An Antigenic Peptide Selectively Modulate T Cell Receptor Binding In A Minimally Perturbing Manner, Kurt H. Piepenbrink, Oleg Y. Borbulevych, Ruth F. Sommese, John Clemens, Kathrynq M. Armstrong, Clare Desmond, Priscilla Do, Brian M. Baker
Food for Health: Publications
T cell receptor (TCR) recognition of antigenic peptides bound and presented by major histocompatibility complex (MHC) molecules forms the basis of the cellular immune response to pathogens and cancer. TCRs bind peptide/MHC molecules weakly and with fast kinetics, features which have hindered detailed biophysical studies of these interactions. Modified peptides resulting in enhanced TCR binding could help overcome these challenges. Further, there is considerable interest in using modified peptides with enhanced TCR binding as the basis for clinical vaccines. Here, we studied how fluorine substitutions in an antigenic peptide can selectively impact TCR recognition. Using a structure-guided design approach, we …
T Cell Receptor Cross-Reactivity Directed By Antigen-Dependent Tuning Of Peptide-Mhc Molecular Flexibility, Oleg Y. Borbulevych, Kurt H. Piepenbrink, Brian E. Gloor, Daniel R. Scott, Ruth F. Sommese, David K. Cole, Andrew K. Sewell, Brian M. Baker
T Cell Receptor Cross-Reactivity Directed By Antigen-Dependent Tuning Of Peptide-Mhc Molecular Flexibility, Oleg Y. Borbulevych, Kurt H. Piepenbrink, Brian E. Gloor, Daniel R. Scott, Ruth F. Sommese, David K. Cole, Andrew K. Sewell, Brian M. Baker
Food for Health: Publications
Tell mediated immunity requires T cell receptor (TCR) cross-reactivity, the mechanisms behind which remain incompletely elucidated. The αβ TCR A6 recognizes both the Tax (LLFGYPVYV) and Tel1p (MLWGYLQYV) peptides presented by the human class I MHC molecule HLA-A2. Here we found that although the two ligands are ideal structural mimics, they form substantially different interfaces with A6, with conformational differences in the peptide, the TCR, and unexpectedly, the MHC molecule. The differences between the Tax and Tel1p ternary complexes could not be predicted from the free peptide-MHC structures and are inconsistent with a traditional induced-fit mechanism. Instead, the differences were …
Conformational Changes And Flexibility In T-Cell Receptor Recognition Of Peptide–Mhc Complexes, Kathryn M. Armstrong, Kurt H. Piepenbrink, Brian M. Baker
Conformational Changes And Flexibility In T-Cell Receptor Recognition Of Peptide–Mhc Complexes, Kathryn M. Armstrong, Kurt H. Piepenbrink, Brian M. Baker
Food for Health: Publications
A necessary feature of the immune system, TCR (T-cell receptor) cross-reactivity has been implicated in numerous autoimmune pathologies and is an underlying cause of transplant rejection. Early studies of the interactions of αβ TCRs (T-cell receptors) with their peptide–MHC ligands suggested that conformational plasticity in the TCR CDR (complementarity determining region) loops is a dominant contributor to T-cell cross-reactivity. Since these initial studies, the database of TCRs whose structures have been solved both bound and free is now large enough to permit general conclusions to be drawn about the extent of TCR plasticity and the types and locations of motion …