Researchers have discovered the mechanisms underlying the immunosuppressive function of a T cell receptor, according to a study published in Nature Immunology, findings that may provide information on the development of new precision therapies for chronic diseases, including cancer.
Hui Zhang, PhD, Professor of Preventive Medicine in the Division of Biostatistics, Member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, and Director of the Biostatistics and Bioinformatics Core of Lurie Cancer Brain Tumor and the Core of Biostatistics and Management of data. at the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, he co-authored the study.
LAG3 is an immune control receptor expressed on the surface of depleted T cells, which progressively lose their immune functions as they fight chronic infection or cancer. As an immune control point, LAG3 inhibits host cell activation and promotes an immunosuppressive response.
Although LAG3-targeted immunotherapy treatments continue to be evaluated in clinical trials, the mechanisms by which LAG3 inhibits T cell function and the appropriate immune response have not been studied.
In the current study, researchers analyzed CD4 + and CD8 + T cells in mice and found that LAG3 moves to the immune synapse, the space between an antigen-presenting cell and the cell. immune, and binds to the T cell receptor (TCR) CD3 protein complex.
The researchers noted that this relocation occurred instead of binding of LAG3 to class II molecules of the major histocompatibility complex (MHC), which are found in antigen-presenting cells and are essential for initiating a. adequate immune response.
Using two super-resolution microscopy techniques: Stimulated Emission Exhaust Microscopy (STED) and Stochastic Optical Reconstruction Microscopy (STORM), the researchers found that LAG3 was co-located with the TCR-CD3 complex in the cells. CD4 + and CD8 + T cells, resulting in loss of fit. TCR signaling and decreased T cell activation.
To identify and quantify data from a single molecule based on STED and STORM coordinates, the researchers used an innovative statistical method proposed by Zhang’s laboratory, the statistical standard for spatial intensity correlation (NSInC), which allows an unbiased analysis of simple coordinates. molecule data to determine which identified proteins are colocalized in three-dimensional space.
“These observations indicated that LAG3 functioned as a signal disruptor independently of the class II major histocompatibility complex and provide information on the mechanism of action of LAG3-targeted immunotherapies,” the authors wrote.
Because current LAG3-targeted cancer therapies block the LAG3-MHC class II interaction, the findings may help in the development of LAG3-targeted therapies and the LAG3-TCR association, as well as for the treatment of autoimmune diseases and inflammatory, according to the authors. .
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Magazine reference:
Guy, C., et al. (2022) LAG3 is associated with TCR-CD3 complexes and suppresses signaling by promoting co-receptor-Lck dissociation. Immunology of nature. doi.org/10.1038/s41590-022-01176-4.