LAG3, also known as CD223, is an immune checkpoint receptor. It plays a crucial role in controlling overt immune activation to prevent autoimmunity by transmitting inhibitory signals to T cells upon binding to ligands like MHC class II, FGL1, and TCR-CD3 complex. Its dysregulation, especially persistent up-regulation in the tumor microenvironment, contributes to T-cell exhaustion, impairing proliferation and cytokine production, thus making it a significant target for cancer immunotherapy [1,2,3].

A Treg cell-specific Lag3 -mutant mouse model showed that Lag3 was essential for Treg cell control of autoimmunity. RNA sequencing analysis revealed that Lag3 mutation altered genes associated with metabolic processes, especially Myc target genes. Myc expression in Lag3 -mutant Treg cells was increased, correlating with changes in metabolic profiles and in vivo suppressive functions. Inhibiting the activated PI3K-Akt-Rictor pathway or Ldha (a key Myc target enzyme) restored normal metabolism and suppressive function in these cells, indicating that Lag3 supports Treg cell suppression by tuning Myc-dependent metabolic programming [4].

In conclusion, LAG3 is vital in maintaining immune tolerance, especially through its role in Treg cells. The study of LAG3 using gene-knockout mouse models has provided insights into its function in autoimmunity, highlighting its potential as a therapeutic target in diseases where immune dysregulation occurs.

References:

1. Andrews, Lawrence P, Marciscano, Ariel E, Drake, Charles G, Vignali, Dario A A. . LAG3 (CD223) as a cancer immunotherapy target. In Immunological reviews, 276, 80-96. doi:10.1111/imr.12519. https://pubmed.ncbi.nlm.nih.gov/28258692/

2. Shi, An-Ping, Tang, Xi-Yang, Xiong, Yan-Lu, Ma, Nan, Zhao, Jin-Bo. 2022. Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer. In Frontiers in immunology, 12, 785091. doi:10.3389/fimmu.2021.785091. https://pubmed.ncbi.nlm.nih.gov/35111155/

3. Mariuzza, Roy A, Shahid, Salman, Karade, Sharanbasappa S. 2024. The immune checkpoint receptor LAG3: Structure, function, and target for cancer immunotherapy. In The Journal of biological chemistry, 300, 107241. doi:10.1016/j.jbc.2024.107241. https://pubmed.ncbi.nlm.nih.gov/38556085/

4. Kim, Dongkyun, Kim, Giha, Yu, Rongzhen, Weinberg, Samuel, Min, Booki. 2024. Inhibitory co-receptor Lag3 supports Foxp3+ regulatory T cell function by restraining Myc-dependent metabolic programming. In Immunity, 57, 2634-2650.e5. doi:10.1016/j.immuni.2024.08.008. https://pubmed.ncbi.nlm.nih.gov/39236718/