特別演講 - 駱宛琳 博士

駱宛琳 博士
Wan-Lin Lo, Ph.D.

Postdoctoral Fellow
Department of Medicine,
University of California San Francisco, USA



演講題目:Modu-LAT-ing T cell self/non-self ligand discrimination
時間:109年 04月 22日 星期一 13:00 - 15:00
地點:長庚大學 第二醫學大樓B1 會議廳一


Scientific abstract

T cell responses are remarkable for their high sensitivity, high specificity, and high speed. Foreign antigens are presented to T cell antigen receptors (TCRs) on T cells by specialized antigen presenting cells (APCs) which utilize major histocompatibility complexes (MHCs) to bind self and foreign peptides derived from encountered pathogens (termed pMHC). T cells can respond to very few foreign pMHC ligands, with a small error rate (10-4 to 10-6) and quick response time (1-5 minutes). This rapid, accurate responsiveness allows T cells to detect foreign pathogens or abnormal cells early and efficiently without reacting to self-tissues. Notably, deregulation of this fine balance of T cell responses leads to catastrophic autoimmune diseases. So, how do T cells tune their ability to distinguish self/non-self? Several factors, including the subtle differences in TCR-pMHC off-rates, on-rates, and affinities, have been proposed to affect T cell discrimination and correlate with responsiviness. However, differences in the binding affinities and kinetics of agonist and non-agonist ligands are not always sufficient to explain actual T cell error rate. Moreover, two TCRs with identical affinities for their cognate pMHCs can elicit distinct patterns of immune responses against bacterial infections. Thus, other factors must exist to explain T cell ligand discrimination, e.g., the kinetic proofreading model. In
this seminar and during the visit to the Chang Gung University, I will discuss how T cells may utilize a series of biochemical reactions to generate the essential “molecular time delay” to “proofread” the interaction between TCR and pMHC, and thus only allow the bona-fide activation signal to propagate downstream. Furthermore, I will discuss how cold-blooded vertebrates and warm-blooded mammals may utilize different kinetic of the same proofreading node to achieve immune-fitness advantages in their living environments for better T cell ligand discrimination. The work is built upon the kinase specificity and biochemistry analysis, and elucidates how a molecular-level signaling event may determine the complex cellular phenotypes of T cell ligand discrimination capability. Finally, given the intense interest in the function and success of chimeric antigen receptors, our insights may provide new opportunities to improve the function of CAR-T cell in therapy of human diseases. Most neoantigens in cancer immunotherapies are derived from self-proteins. The insights from the work here provides an approach to engineer an otherwise weak anti-tumor TCR recognition event into one with enhanced protective tumor immunity.
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