{"548621":{"#nid":"548621","#data":{"type":"event","title":"PhD Defense by Kaitao Li","body":[{"value":"\u003Cp\u003E\u003Cstrong\u003EKaitao Li\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003EBME PhD Defense Presentation\u003C\/p\u003E\u003Cp\u003EDate:\u0026nbsp;July 11th, 2016\u003C\/p\u003E\u003Cp\u003ETime:\u0026nbsp;11AM\u003C\/p\u003E\u003Cp\u003ELocation:\u0026nbsp;IBB 1128\u003C\/p\u003E\u003Cp\u003E\u0026nbsp;\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EAdvisor:\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003ECheng Zhu, PhD (Georgia Institute of Technology)\u003C\/p\u003E\u003Cp\u003E\u003Cbr \/\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EThesis Committee Members:\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003ESimon J. Davis, PhD (Oxford University)\u003C\/p\u003E\u003Cp\u003EArash Grakoui, PhD (Emory University)\u003C\/p\u003E\u003Cp\u003EMelissa L. Kemp, PhD (Georgia Institute of Technology)\u003C\/p\u003E\u003Cp\u003ESusan Thomas, PhD (Georgia Institute of Technology)\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003E\u0026nbsp;\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003ETitle:\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003E2D kinetic study of PD-1 interaction and its inhibition of T cell antigen recognition\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u0026nbsp;\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EAbstract\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003EProgrammed death-1 (PD-1) is an immune-checkpoint receptor with its primary function to maintain peripheral tolerance of the adaptive immune responses. The importance of PD-1 is evidenced by its deficiency leading to autoimmune disorders, its central role in the identification and restoration of the exhausted phenotypes of antigen-specific T cells, and the great success in targeting this pathway for cancer immunotherapy. To better understand the fundamental question as how PD-1 achieves the potent but well-controlled inhibition, we applied kinetic approaches focusing on its\u0026nbsp;\u003Cem\u003Ein situ\u003C\/em\u003E\u0026nbsp;ligand binding characteristics, and the early impact on antigen recognition by the T cell receptor (TCR) and coreceptor CD8. Different from the weak three-dimensional (3D) affinities measured in solution using purified PD-1 and ligands, the two-dimensional (2D) affinities of ligand binding to mouse and human PD-1 expressed on cell membrane span a range from middle to strong, whereas PD-L1\u2013B7-1 binding is much weaker. Comparison of 2D and 3D affinities of TCR, costimulatory, and coinhibitory receptors reveals differential enhancement of in situ ligand binding for various receptors by the cellular environment. By integrating the 2D kinetic analysis of PD-1 with TCR and CD8, we probed an apparent \u201cnegative cooperativity\u201d between these two axis, manifested as reduced molecular bond number and bond lifetime when respective ligands were co-presented. Examination with force spectroscopy suggests the \u201cnegative cooperativity\u201d to be the net outcome of suppressed \u201cpositive cooperativity\u201d between TCR and CD8. Moreover, the dependence of this suppression on Src homology region 2 domain-containing phosphatase-2 (SHP-2) and lymphocyte-specific protein tyrosine kinase (Lck) further identified it as a \u201cbinding-signaling-binding\u201d feedback mechanism representing fine-tuning of antigen recognition by coinhibitory receptors via targeting the TCR-CD8 machinery. Overall, our results provide an in depth understanding of the in situ interaction and function of PD-1, highlighting the complexity and significance of costimulatory\/coinhibitory molecules in modulating T cell responses.\u003C\/p\u003E\u003Cp\u003E\u0026nbsp;\u003C\/p\u003E\u003Cp\u003E \u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":"","field_summary_sentence":[{"value":"2D kinetic study of PD-1 interaction and its inhibition of T cell antigen recognition"}],"uid":"27707","created_gmt":"2016-06-28 09:01:22","changed_gmt":"2016-10-08 02:18:11","author":"Tatianna Richardson","boilerplate_text":"","field_publication":"","field_article_url":"","field_event_time":{"event_time_start":"2016-07-11T12:00:00-04:00","event_time_end":"2016-07-11T14:00:00-04:00","event_time_end_last":"2016-07-11T14:00:00-04:00","gmt_time_start":"2016-07-11 16:00:00","gmt_time_end":"2016-07-11 18:00:00","gmt_time_end_last":"2016-07-11 18:00:00","rrule":null,"timezone":"America\/New_York"},"extras":[],"groups":[{"id":"221981","name":"Graduate Studies"}],"categories":[],"keywords":[{"id":"100811","name":"Phd Defense"}],"core_research_areas":[],"news_room_topics":[],"event_categories":[{"id":"1788","name":"Other\/Miscellaneous"}],"invited_audience":[{"id":"78771","name":"Public"}],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[],"email":[],"slides":[],"orientation":[],"userdata":""}}}