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Immune mechanisms

T cells are pivotal elements of the adaptive immune system. Their effector functions are governed by two primary factors: the specific recognition facilitated by the T cell receptor (TCR) and the functional modulation arising from the interactions between activating/inhibitory immune regulatory receptors and their corresponding ligands. These interactions ensure the precision and efficacy of immune responses. Understanding the mechanisms of antigen presentation and the molecular underpinnings of immune receptor/ligand recognition is essential for comprehending immune response and regulation processes. Moreover, this knowledge provides vital theoretical foundations for the development of novel immunotherapeutic strategies. Notable advancements in the study of T cell immune recognition and response mechanisms include:

  1. MHC Class I Antigen      Presentation and TCR Recognition Mechanisms

l  By elucidating the molecular basis of CD8αα binding to HLA-A2, the fundamental recognition mechanism between these critical immune molecules on the T cell surface was uncovered (1997 Nature cover; 2000 Immunity-a, -b; 2011 Mol Immunol, etc.).

l  The molecular mechanisms underlying antigen presentation by MHC class I molecules across diverse species and their recognition by the T cell receptor (TCR) were clarified, offering significant insights into immune evolution and advancing vaccine design strategies (2007, 2011, 2012, 2014, 2016 J Immunol; 2010, 2011, 2017 J Virol, etc.).

Figure 1. Antigen processing, presentation for TCR recognition.

l  A comprehensive system for T cell epitope identification and antigen-specific T cell functional studies was established. A series of T cell epitopes were discovered in critical pathogens such as influenza virus, SARS-CoV, MERS-CoV, and HBV. Systematic research was conducted on the T cell immune response mechanisms during infections caused by significant influenza strains, including pH1N1, H5N6, and H7N9. These findings have provided a crucial foundation for elucidating the immune protection mechanisms of different pathogens, disease diagnosis, and vaccine development (2005, 2006, 2013, 2017, 2018 Journal of Immunology; 2010, 2016 Journal of Infectious Diseases; 2010, 2012 Journal of Virology; 2018 mBio; 2018 Clinical Infectious Diseases, etc.).

l  Through the screening and identification of novel T cell antigens in Mycobacterium tuberculosis (Chinese Patents ZL201210090659.1 and ZL201110362902.6), a "T Cell Immunoassay Kit for Tuberculosis Infection (ELISPOT)" was jointly developed. The kit was approved and granted a medical device registration certificate by the China Food and Drug Administration (Registration No. 3401090, 2014) (2017 Tuberculosis).

  1. Binding mechanisms of PD-1/PD-L1      antibody drugs and the impact of glycosylation modification on the      efficacy of antibody drugs

l  In 2010,we resolved the molecular structure of PD-L1 (Protein & Cell, 2010). For the first time, the team proposed that the influence of glycosylation modification of the PD-1 molecule should be taken into account for antibody drugs. Systematic researches on the binding characteristics and glycosylation dependence of various antibody drugs were conducted (Nature Communications, 2017; EMBO Reports, 2020; mAbs, 2019; EMBO Reports, 2020). Through the study of the binding epitopes of multiple antibodies, it was found that the FG loop of PD-1 might be a potential immunogenic "hotspot" (iScience, 2019; mAbs, 2019). In cooperation with the team led by Bruno Correia from the University of Geneva, Switzerland, the research team carried out the "de novo design" of PD-1/PD-L1 binding proteins, providing an important basis for the development of new immunotherapeutic drugs (Nature, 2023).

l  The molecular basis of the binding of avelumab and durvalumab to PD-L1 was deciphered, providing critical insights into the binding mechanisms of different PD-L1 antibody drugs (2017, Cell Research; 2018, Protein & Cell). Studies revealed that the interactions between JS003 and BMS-936559 antibodies with PD-L1 exhibit significant pH dependency, offering a theoretical foundation for understanding the factors influencing the activity of different PD-L1 antibody drugs in the tumor microenvironment (2020, Signal Transduction and Targeted Therapy).

Figure 2. Binding mechanisms of PD-1/PD-L1 specific antibodies

 

l  Building on the research foundation of PD-1/PD-L1 antibody drug mechanisms and leveraging the technological advantages of the T cell immune platform, an immune checkpoint antibody drug screening and evaluation platform was established. Notably, a PD-1 antibody developed through this platform received approval for clinical trials from the National Medical Products Administration (Approval Notice No.: 2020LP00409).

  1. Ligand Recognition Mechanisms      of T Cell/NK Cell Immune Regulatory Receptor Molecules

l  Ligand Recognition Mechanisms of Key Activating Receptors in the TNF Superfamily. The ligand recognition mechanisms of critical activating receptors within the TNF superfamily were systematically investigated. Specifically, the mechanisms by which 4-1BB and GITR ligands diverge from the classical "TNF/TNFR" family recognition patterns were elucidated. These findings advance our understanding of the evolutionary principles governing TNFR/TNF superfamily molecule recognition and provide valuable insights for the development of therapeutic agents targeting 4-1BB and GITR (2018, Cell Reports; 2021, Cell Reports).

l  The unique molecular architecture of CD226 and its molecular basis for recognizing the ligand CD155 were uncovered. This discovery establishes a theoretical foundation for understanding the interaction mechanisms between CD226 and its ligands, as well as for the development of activating antibody drugs targeting CD226. Additionally, the molecular mechanism underlying CD112R's recognition of its ligand CD112 was deciphered (2019, PNAS; 2024, Structure cover story).

Figure 3. NK cell immune regulatory receptor/ligands and recognition of CD226/CD155

l  We conducted a comprehensive investigation into the molecular mechanisms governing the interactions between Nectin/Nectin-like family molecules and their associated receptor molecules, as well as with proteins from HSV and measles viruses. Additionally, the interaction mechanisms between LILR/ILT family molecules and their ligands were elucidated. These findings hold significant implications for advancing our understanding of immune regulatory mechanisms, shedding light on how viruses hijack immune molecules to facilitate host invasion, and informing the development of targeted therapeutic strategies (2011, Nature Communications; 2012, Journal of Immunology; 2013, Nature Structural & Molecular Biology, Structure; 2017, PLOS Pathogens, etc.). Furthermore, the team systematically explored the interaction mechanisms between immune molecules, such as OSCAR and PILR, and their respective ligands (2014, 2016, PNAS).