The Experts below are selected from a list of 3705 Experts worldwide ranked by ideXlab platform
Jamie Rossjohn - One of the best experts on this subject based on the ideXlab platform.
-
Understanding the drivers of MHC Restriction of T cell receptors
Nature reviews. Immunology, 2018Co-Authors: Nicole L. La Gruta, Stephanie Gras, Stephen R. Daley, Paul G. Thomas, Jamie RossjohnAbstract:T cell discrimination of self and non-self is predicated on αβ T cell receptor (TCR) co-recognition of peptides presented by MHC molecules. Over the past 20 years, structurally focused investigations into this MHC-restricted response have provided profound insights into T cell function. Simultaneously, two models of TCR recognition have emerged, centred on whether the TCR has, through evolution, acquired an intrinsic germline-encoded capacity for MHC recognition or whether MHC reactivity is conferred by developmental selection of TCRs. Here, we review the structural and functional data that pertain to these theories of TCR recognition, which indicate that it will be necessary to assimilate features of both models to fully account for the molecular drivers of this evolutionarily ancient interaction between the TCR and MHC molecules.
-
t cell allorecognition and MHC Restriction a case of jekyll and hyde
Molecular Immunology, 2008Co-Authors: J K Archbold, James Mccluskey, Jamie Rossjohn, Lars Kjernielsen, Scott R Burrows, W A MacdonaldAbstract:A great paradox in cellular immunology is how T cell allorecognition exists at high frequencies (up to 10%) despite the stringent requirements of discriminating ‘self’ from ‘non-self’ imposed by MHC Restriction. Thus, in tissue transplantation, a substantial proportion of the recipient's T cells will have the ability to recognize the graft and instigate an immune response against the transplanted tissue, ultimately resulting in graft rejection—a manifestation of T cell alloreactivity. Transplantation of human organs and lymphoid cells as treatment for otherwise life-threatening diseases has become a more routine medical procedure making this problem of great importance. Immunologists have gained important insights into the mechanisms of T cell alloreactivity from cytotoxic T cell assays, affinity-avidity studies, and crystal structures of peptide-MHC (pMHC) molecules and T cell receptors (TCRs) both alone and in complex. Despite the clinical significance of alloreactivity, the crystal structure of an alloreactive human TCR in complex with both cognate pMHC and an allogeneic pMHC complex has yet to be determined. This review highlights some of the important findings from studies characterizing the way in which alloreactive T cell receptors and pMHC molecules interact in an attempt to resolve this great irony of the cellular immune response.
-
TCRα Genes Direct MHC Restriction in the Potent Human T Cell Response to a Class I-Bound Viral Epitope
Journal of immunology (Baltimore Md. : 1950), 2006Co-Authors: John J. Miles, Lars Kjer-nielsen, James Mccluskey, Natalie A. Borg, Rebekah M Brennan, Fleur Elizabeth Tynan, Sharon L. Silins, Melissa J. Bell, Jacqueline M. Burrows, Jamie RossjohnAbstract:The underlying generic properties of αβ TCRs that control MHC Restriction remain largely unresolved. To investigate MHC Restriction, we have examined the CTL response to a viral epitope that binds promiscuously to two human leukocyte Ags (HLAs) that differ by a single amino acid at position 156. Individuals expressing either HLA-B*3501 (156Leucine) or HLA-B*3508 (156Arginine) showed a potent CTL response to the 407HPVGEADYFEY417 epitope from EBV. Interestingly, the response was characterized by highly restricted TCR β-chain usage in both HLA-B*3501+ and HLA-B*3508+ individuals; however, this conserved TRBV9+ β-chain was associated with distinct TCR α-chains depending upon the HLA-B*35 allele expressed by the virus-exposed host. Functional assays confirmed that TCR α-chain usage determined the HLA Restriction of the CTLs. Structural studies revealed significant differences in the mobility of the peptide when bound to HLA-B*3501 or HLA-B*3508. In HLA-B*3501, the bulged section of the peptide was disordered, whereas in HLA-B*3508 the bulged epitope adopted an ordered conformation. Collectively, these data demonstrate not only that mobile MHC-bound peptides can be highly immunogenic but can also stimulate an extremely biased TCR repertoire. In addition, TCR α-chain usage is shown to play a critical role in controlling MHC Restriction between closely related allomorphs.
-
disparate thermodynamics governing t cell receptor MHC i interactions implicate extrinsic factors in guiding MHC Restriction
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Lauren Kate Ely, Travis Clarke Beddoe, Craig Steven Clements, Jacqueline M. Matthews, Anthony W. Purcell, James Mccluskey, Lars Kjernielsen, Jamie RossjohnAbstract:The underlying basis of major histocompatibility complex (MHC) Restriction is unclear. Nevertheless, current data suggest that a common thermodynamic signature dictates αβ T cell receptor (TcR) ligation. To evaluate whether this thermodynamic signature defines MHC Restriction, we have examined the thermodynamic basis of a highly characterized immunodominant TcR interacting with its cognate peptide–MHC-I ligand. Surprisingly, we observed this interaction to be governed by favorable enthalpic and entropic forces, which is in contrast to the prevailing generality, namely, enthalpically driven interactions combined with markedly unfavorable entropic forces. We conclude that extrinsic molecular factors, such as coreceptor ligation, conformational adjustments involved in TcR signaling, or constraints dictated by higher-order arrangement of ligated TcRs, might play a greater role in guiding MHC Restriction than appreciated previously.
-
Disparate thermodynamics governing T cell receptor–MHC-I interactions implicate extrinsic factors in guiding MHC Restriction
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Lauren Kate Ely, Travis Clarke Beddoe, Craig Steven Clements, Jacqueline M. Matthews, Anthony W. Purcell, Lars Kjer-nielsen, James Mccluskey, Jamie RossjohnAbstract:The underlying basis of major histocompatibility complex (MHC) Restriction is unclear. Nevertheless, current data suggest that a common thermodynamic signature dictates αβ T cell receptor (TcR) ligation. To evaluate whether this thermodynamic signature defines MHC Restriction, we have examined the thermodynamic basis of a highly characterized immunodominant TcR interacting with its cognate peptide–MHC-I ligand. Surprisingly, we observed this interaction to be governed by favorable enthalpic and entropic forces, which is in contrast to the prevailing generality, namely, enthalpically driven interactions combined with markedly unfavorable entropic forces. We conclude that extrinsic molecular factors, such as coreceptor ligation, conformational adjustments involved in TcR signaling, or constraints dictated by higher-order arrangement of ligated TcRs, might play a greater role in guiding MHC Restriction than appreciated previously.
Pamela J. Bjorkman - One of the best experts on this subject based on the ideXlab platform.
-
MHC Restriction in three dimensions: a view of T cell receptor/ligand interactions.
Cell, 1997Co-Authors: Pamela J. BjorkmanAbstract:B and T lymphocytes of the immune system employ a highly effective diversity-generating machinery to ensure that their receptors, antibodies and T cell receptors (TCRs), respectively, have the capacity to recognize an enormous array of antigens. Indeed, antibodies can be raised against many kinds of molecules that are perceived as foreign to the host, including proteins, carbohydrates, small organic compounds, and nucleic acids. TCRs, on the other hand, have the seemingly peculiar property that they only recognize a foreign antigen when it is associated with a host- or “self”-encoded protein called a major histocompatibility complex (MHC) molecule. The T cell property of “MHC-restricted” recognition of antigen was discovered for cytotoxic T cells by Zinkernagel and Doherty 1974, work for which they received the 1996 Nobel Prize in Medicine.
-
MHC Restriction in three dimensions a view of t cell receptor ligand interactions
Cell, 1997Co-Authors: Pamela J. BjorkmanAbstract:B and T lymphocytes of the immune system employ a highly effective diversity-generating machinery to ensure that their receptors, antibodies and T cell receptors (TCRs), respectively, have the capacity to recognize an enormous array of antigens. Indeed, antibodies can be raised against many kinds of molecules that are perceived as foreign to the host, including proteins, carbohydrates, small organic compounds, and nucleic acids. TCRs, on the other hand, have the seemingly peculiar property that they only recognize a foreign antigen when it is associated with a host- or “self”-encoded protein called a major histocompatibility complex (MHC) molecule. The T cell property of “MHC-restricted” recognition of antigen was discovered for cytotoxic T cells by Zinkernagel and Doherty 1974, work for which they received the 1996 Nobel Prize in Medicine.
Ramila Philip - One of the best experts on this subject based on the ideXlab platform.
-
MHC-unrestricted lysis of MUC1-expressing cells by human peripheral blood mononuclear cells.
Immunological investigations, 2008Co-Authors: Stephen E. Wright, Kathleen Rewers-felkins, Imelda S. Quinlin, William E. Fogler, Catherine A. Phillips, Mary Townsend, William R. Robinson, Ramila PhilipAbstract:Many human adenocarcinomas can be killed in vitro by targeted cytotoxic T-lymphocytes (CTL); however, major histocompatibility complex (MHC)-Restrictions are typically required. The MUC1 antigen is common in many human adenocarcinomas, and is associated with a variable number of tandem repeats. It has been proposed that antigens with such repeated epitopes may be vulnerable to cytotoxic T-lymphocyte killing without MHC-Restriction. Therefore, it is possible that MUC1-expressing malignant cells may be killed by targeted cytotoxic T-lymphocyte in the absence of MHC-Restriction. In this study, a human MUC1-expressing murine mammary carcinoma cell line was used to determine if cytotoxic T-lymphocyte killing of MUC1-expressing adenocarcinoma cells requires MHC-Restriction. Specifically, MUC1-stimulated human mononuclear cells (M1SMC) were observed to kill human MUC1-transfected, MUC1-expressing murine mammary carcinoma cells, but not the mock-transfected, non-MUC1-expressing murine mammary carcinoma cells. Fur...
James Mccluskey - One of the best experts on this subject based on the ideXlab platform.
-
t cell allorecognition and MHC Restriction a case of jekyll and hyde
Molecular Immunology, 2008Co-Authors: J K Archbold, James Mccluskey, Jamie Rossjohn, Lars Kjernielsen, Scott R Burrows, W A MacdonaldAbstract:A great paradox in cellular immunology is how T cell allorecognition exists at high frequencies (up to 10%) despite the stringent requirements of discriminating ‘self’ from ‘non-self’ imposed by MHC Restriction. Thus, in tissue transplantation, a substantial proportion of the recipient's T cells will have the ability to recognize the graft and instigate an immune response against the transplanted tissue, ultimately resulting in graft rejection—a manifestation of T cell alloreactivity. Transplantation of human organs and lymphoid cells as treatment for otherwise life-threatening diseases has become a more routine medical procedure making this problem of great importance. Immunologists have gained important insights into the mechanisms of T cell alloreactivity from cytotoxic T cell assays, affinity-avidity studies, and crystal structures of peptide-MHC (pMHC) molecules and T cell receptors (TCRs) both alone and in complex. Despite the clinical significance of alloreactivity, the crystal structure of an alloreactive human TCR in complex with both cognate pMHC and an allogeneic pMHC complex has yet to be determined. This review highlights some of the important findings from studies characterizing the way in which alloreactive T cell receptors and pMHC molecules interact in an attempt to resolve this great irony of the cellular immune response.
-
TCRα Genes Direct MHC Restriction in the Potent Human T Cell Response to a Class I-Bound Viral Epitope
Journal of immunology (Baltimore Md. : 1950), 2006Co-Authors: John J. Miles, Lars Kjer-nielsen, James Mccluskey, Natalie A. Borg, Rebekah M Brennan, Fleur Elizabeth Tynan, Sharon L. Silins, Melissa J. Bell, Jacqueline M. Burrows, Jamie RossjohnAbstract:The underlying generic properties of αβ TCRs that control MHC Restriction remain largely unresolved. To investigate MHC Restriction, we have examined the CTL response to a viral epitope that binds promiscuously to two human leukocyte Ags (HLAs) that differ by a single amino acid at position 156. Individuals expressing either HLA-B*3501 (156Leucine) or HLA-B*3508 (156Arginine) showed a potent CTL response to the 407HPVGEADYFEY417 epitope from EBV. Interestingly, the response was characterized by highly restricted TCR β-chain usage in both HLA-B*3501+ and HLA-B*3508+ individuals; however, this conserved TRBV9+ β-chain was associated with distinct TCR α-chains depending upon the HLA-B*35 allele expressed by the virus-exposed host. Functional assays confirmed that TCR α-chain usage determined the HLA Restriction of the CTLs. Structural studies revealed significant differences in the mobility of the peptide when bound to HLA-B*3501 or HLA-B*3508. In HLA-B*3501, the bulged section of the peptide was disordered, whereas in HLA-B*3508 the bulged epitope adopted an ordered conformation. Collectively, these data demonstrate not only that mobile MHC-bound peptides can be highly immunogenic but can also stimulate an extremely biased TCR repertoire. In addition, TCR α-chain usage is shown to play a critical role in controlling MHC Restriction between closely related allomorphs.
-
disparate thermodynamics governing t cell receptor MHC i interactions implicate extrinsic factors in guiding MHC Restriction
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Lauren Kate Ely, Travis Clarke Beddoe, Craig Steven Clements, Jacqueline M. Matthews, Anthony W. Purcell, James Mccluskey, Lars Kjernielsen, Jamie RossjohnAbstract:The underlying basis of major histocompatibility complex (MHC) Restriction is unclear. Nevertheless, current data suggest that a common thermodynamic signature dictates αβ T cell receptor (TcR) ligation. To evaluate whether this thermodynamic signature defines MHC Restriction, we have examined the thermodynamic basis of a highly characterized immunodominant TcR interacting with its cognate peptide–MHC-I ligand. Surprisingly, we observed this interaction to be governed by favorable enthalpic and entropic forces, which is in contrast to the prevailing generality, namely, enthalpically driven interactions combined with markedly unfavorable entropic forces. We conclude that extrinsic molecular factors, such as coreceptor ligation, conformational adjustments involved in TcR signaling, or constraints dictated by higher-order arrangement of ligated TcRs, might play a greater role in guiding MHC Restriction than appreciated previously.
-
Disparate thermodynamics governing T cell receptor–MHC-I interactions implicate extrinsic factors in guiding MHC Restriction
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Lauren Kate Ely, Travis Clarke Beddoe, Craig Steven Clements, Jacqueline M. Matthews, Anthony W. Purcell, Lars Kjer-nielsen, James Mccluskey, Jamie RossjohnAbstract:The underlying basis of major histocompatibility complex (MHC) Restriction is unclear. Nevertheless, current data suggest that a common thermodynamic signature dictates αβ T cell receptor (TcR) ligation. To evaluate whether this thermodynamic signature defines MHC Restriction, we have examined the thermodynamic basis of a highly characterized immunodominant TcR interacting with its cognate peptide–MHC-I ligand. Surprisingly, we observed this interaction to be governed by favorable enthalpic and entropic forces, which is in contrast to the prevailing generality, namely, enthalpically driven interactions combined with markedly unfavorable entropic forces. We conclude that extrinsic molecular factors, such as coreceptor ligation, conformational adjustments involved in TcR signaling, or constraints dictated by higher-order arrangement of ligated TcRs, might play a greater role in guiding MHC Restriction than appreciated previously.
Craig Steven Clements - One of the best experts on this subject based on the ideXlab platform.
-
disparate thermodynamics governing t cell receptor MHC i interactions implicate extrinsic factors in guiding MHC Restriction
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Lauren Kate Ely, Travis Clarke Beddoe, Craig Steven Clements, Jacqueline M. Matthews, Anthony W. Purcell, James Mccluskey, Lars Kjernielsen, Jamie RossjohnAbstract:The underlying basis of major histocompatibility complex (MHC) Restriction is unclear. Nevertheless, current data suggest that a common thermodynamic signature dictates αβ T cell receptor (TcR) ligation. To evaluate whether this thermodynamic signature defines MHC Restriction, we have examined the thermodynamic basis of a highly characterized immunodominant TcR interacting with its cognate peptide–MHC-I ligand. Surprisingly, we observed this interaction to be governed by favorable enthalpic and entropic forces, which is in contrast to the prevailing generality, namely, enthalpically driven interactions combined with markedly unfavorable entropic forces. We conclude that extrinsic molecular factors, such as coreceptor ligation, conformational adjustments involved in TcR signaling, or constraints dictated by higher-order arrangement of ligated TcRs, might play a greater role in guiding MHC Restriction than appreciated previously.
-
Disparate thermodynamics governing T cell receptor–MHC-I interactions implicate extrinsic factors in guiding MHC Restriction
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Lauren Kate Ely, Travis Clarke Beddoe, Craig Steven Clements, Jacqueline M. Matthews, Anthony W. Purcell, Lars Kjer-nielsen, James Mccluskey, Jamie RossjohnAbstract:The underlying basis of major histocompatibility complex (MHC) Restriction is unclear. Nevertheless, current data suggest that a common thermodynamic signature dictates αβ T cell receptor (TcR) ligation. To evaluate whether this thermodynamic signature defines MHC Restriction, we have examined the thermodynamic basis of a highly characterized immunodominant TcR interacting with its cognate peptide–MHC-I ligand. Surprisingly, we observed this interaction to be governed by favorable enthalpic and entropic forces, which is in contrast to the prevailing generality, namely, enthalpically driven interactions combined with markedly unfavorable entropic forces. We conclude that extrinsic molecular factors, such as coreceptor ligation, conformational adjustments involved in TcR signaling, or constraints dictated by higher-order arrangement of ligated TcRs, might play a greater role in guiding MHC Restriction than appreciated previously.
-
T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I-bound peptide.
Nature immunology, 2005Co-Authors: Fleur Elizabeth Tynan, Travis Clarke Beddoe, Craig Steven Clements, John J. Miles, Natalie A. Borg, Scott R Burrows, Ashley M. Buckle, James C. Whisstock, Matthew C. J. Wilce, Sharon L. SilinsAbstract:Unusually long major histocompatibility complex (MHC) class I-restricted epitopes are important in immunity, but their 'bulged' conformation represents a potential obstacle to alphabeta T cell receptor (TCR)-MHC class I docking. To elucidate how such recognition is achieved while still preserving MHC Restriction, we have determined here the structure of a TCR in complex with HLA-B(*)3508 presenting a peptide 13 amino acids in length. This complex was atypical of TCR-peptide-MHC class I interactions, being dominated at the interface by peptide-mediated interactions. The TCR assumed two distinct orientations, swiveling on top of the centrally bulged, rigid peptide such that only limited contacts were made with MHC class I. Although the TCR-peptide recognition resembled an antibody-antigen interaction, the TCR-MHC class I contacts defined a minimal 'generic footprint' of MHC-Restriction. Thus our findings simultaneously demonstrate the considerable adaptability of the TCR and the 'shape' of MHC Restriction.