{"id":{"repo_id":"maryland","oai_identifier":"oai:drum.lib.umd.edu:1903/11181"},"canonical_url":"https://search.dev.ndltd.org/etd/maryland/oai:drum.lib.umd.edu:1903/11181","repository":{"repo_id":"maryland","name":"University of Maryland","base_url":"https://api.drum.lib.umd.edu/server/oai/request"},"display":{"title":"Structural basis for escaping negative selection by T cell receptor with high affinity for self antigen","abstract":"The failure to eliminate self-reactive T cells is a prerequisite for autoimmunity. To escape thymic deletion, autoreactive T cell receptors (TCRs) may form relatively unstable complexes with self-peptide-MHC. These TCRs adopt suboptimal docking topologies in striking contrast to the classical topology of anti-microbial TCRs. Alternatively, escape can occur by weak binding between self-peptides and MHC. We determined the structure of a human autoimmune TCR (MS2-3C8) bound to a self-peptide from myelin basic protein (MBP) and the multiple sclerosis-associated MHC molecule HLA-DR4. MS2-3C8 is encephalitogenic in humanized transgenic mice. The structure showed loose accommodation of MBP in the HLA-DR4 binding groove, accounting for its low affinity. By contrast, MS2-3C8 binds MBP-DR4 as tightly as the most avid anti-microbial TCRs. Structurally, MS2-3C8 engages self-antigen via a docking mode that closely resembles the optimal topology of anti-microbial TCRs, but is distinct from that of other autoreactive TCRs. Combined with a unique CDR3 β conformation, this docking mode compensates for the weak binding of MBP to HLA-DR4 by maximizing interactions between MS2-3C8 and MBP. Thus, the MS2-3C8-MBP-DR4 complex reveals the basis for an alternative strategy whereby autoreactive T cells escape negative selection, yet retain the ability to initiate autoimmunity.","abstract_html":"The failure to eliminate self-reactive T cells is a prerequisite for autoimmunity. To escape thymic deletion, autoreactive T cell receptors (TCRs) may form relatively unstable complexes with self-peptide-MHC. These TCRs adopt suboptimal docking topologies in striking contrast to the classical topology of anti-microbial TCRs. Alternatively, escape can occur by weak binding between self-peptides and MHC. We determined the structure of a human autoimmune TCR (MS2-3C8) bound to a self-peptide from myelin basic protein (MBP) and the multiple sclerosis-associated MHC molecule HLA-DR4. MS2-3C8 is encephalitogenic in humanized transgenic mice. The structure showed loose accommodation of MBP in the HLA-DR4 binding groove, accounting for its low affinity. By contrast, MS2-3C8 binds MBP-DR4 as tightly as the most avid anti-microbial TCRs. Structurally, MS2-3C8 engages self-antigen via a docking mode that closely resembles the optimal topology of anti-microbial TCRs, but is distinct from that of other autoreactive TCRs. Combined with a unique CDR3 β conformation, this docking mode compensates for the weak binding of MBP to HLA-DR4 by maximizing interactions between MS2-3C8 and MBP. Thus, the MS2-3C8-MBP-DR4 complex reveals the basis for an alternative strategy whereby autoreactive T cells escape negative selection, yet retain the ability to initiate autoimmunity.","abstract_has_math":false,"creators":["Yin, Yiyuan"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Molecular and Cell Biology","school":null,"contributors":[],"advisors":["Mariuzza, Roy A"],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010","date_published":"2010","updated_at":"2026-07-24T03:02:08Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1903/11181","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Mariuzza, Roy A"]},{"key":"dc:contributor.department","label":"Department","values":["Molecular and Cell Biology"]},{"key":"dc:creator","label":"Author","values":["Yin, Yiyuan"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2011-02-19T06:59:49Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2011-02-19T06:59:49Z"]},{"key":"dc:date.issued","label":"Date","values":["2010"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/1903/11181"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The failure to eliminate self-reactive T cells is a prerequisite for autoimmunity. To escape thymic deletion, autoreactive T cell receptors (TCRs) may form relatively unstable complexes with self-peptide-MHC. These TCRs adopt suboptimal docking topologies in striking contrast to the classical topology of anti-microbial TCRs. Alternatively, escape can occur by weak binding between self-peptides and MHC. We determined the structure of a human autoimmune TCR (MS2-3C8) bound to a self-peptide from myelin basic protein (MBP) and the multiple sclerosis-associated MHC molecule HLA-DR4. MS2-3C8 is encephalitogenic in humanized transgenic mice. The structure showed loose accommodation of MBP in the HLA-DR4 binding groove, accounting for its low affinity. By contrast, MS2-3C8 binds MBP-DR4 as tightly as the most avid anti-microbial TCRs. Structurally, MS2-3C8 engages self-antigen via a docking mode that closely resembles the optimal topology of anti-microbial TCRs, but is distinct from that of other autoreactive TCRs. Combined with a unique CDR3 β conformation, this docking mode compensates for the weak binding of MBP to HLA-DR4 by maximizing interactions between MS2-3C8 and MBP. Thus, the MS2-3C8-MBP-DR4 complex reveals the basis for an alternative strategy whereby autoreactive T cells escape negative selection, yet retain the ability to initiate autoimmunity."]},{"key":"dc:title","label":"Title","values":["Structural basis for escaping negative selection by T cell receptor with high affinity for self antigen"]}]}],"canonical_facts":{"dc:contributor.advisor":["Mariuzza, Roy A"],"dc:contributor.department":["Molecular and Cell Biology"],"dc:creator":["Yin, Yiyuan"],"dc:date.accessioned":["2011-02-19T06:59:49Z"],"dc:date.available":["2011-02-19T06:59:49Z"],"dc:date.issued":["2010"],"dc:description.abstract":["The failure to eliminate self-reactive T cells is a prerequisite for autoimmunity. To escape thymic deletion, autoreactive T cell receptors (TCRs) may form relatively unstable complexes with self-peptide-MHC. These TCRs adopt suboptimal docking topologies in striking contrast to the classical topology of anti-microbial TCRs. Alternatively, escape can occur by weak binding between self-peptides and MHC. We determined the structure of a human autoimmune TCR (MS2-3C8) bound to a self-peptide from myelin basic protein (MBP) and the multiple sclerosis-associated MHC molecule HLA-DR4. MS2-3C8 is encephalitogenic in humanized transgenic mice. The structure showed loose accommodation of MBP in the HLA-DR4 binding groove, accounting for its low affinity. By contrast, MS2-3C8 binds MBP-DR4 as tightly as the most avid anti-microbial TCRs. Structurally, MS2-3C8 engages self-antigen via a docking mode that closely resembles the optimal topology of anti-microbial TCRs, but is distinct from that of other autoreactive TCRs. Combined with a unique CDR3 β conformation, this docking mode compensates for the weak binding of MBP to HLA-DR4 by maximizing interactions between MS2-3C8 and MBP. Thus, the MS2-3C8-MBP-DR4 complex reveals the basis for an alternative strategy whereby autoreactive T cells escape negative selection, yet retain the ability to initiate autoimmunity."],"dc:identifier.uri":["http://hdl.handle.net/1903/11181"],"dc:title":["Structural basis for escaping negative selection by T cell receptor with high affinity for self antigen"],"dc:type":["Dissertation"]},"updated_at":"2026-07-24T03:02:08Z"}