HOMEResearch
Molecular and cellular mechanisms of immune tolerance.
The 2018 Nobel Prize in Physiology or Medicine was awarded to Drs. Tasuku Honjo and James P. Allison for their discovery of cancer therapy by inhibition of negative immune regulation. They demonstrated that the targeted blockade of inhibitory co-receptors, PD-1 and CTLA-4 can destroy tumors by activating tumor-specific T cells. I have engaged in researches such as the identification of PD-1 ligands, elucidation of the inhibitory mechanism of PD-1, dissection of the pathomechanisms of autoimmune diseases that PD-1KO mice develop, and treatments of cancer by PD-1 blockade in Dr. Honjo's laboratory. Through these researches, PD-1 has been established as an inhibitory co-receptor of lymphocytes and proposed to be a promising target of cancer immunotherapy.
Stimulatory and inhibitory co-receptors tightly control the activation of lymphocytes by regulating the quality and the quantity of the antigen receptor signaling to optimize beneficial immune responses while avoiding autoimmunity and excess immune responses. In addition to PD-1 and CTLA-4, many other co-receptors have been identified and regarded as potential drug targets. Although these co-receptors are supposed to have unique function and cooperate each other, their functional differences and coordination remain to be clarified. Therefore, the primary aim of our laboratory is to elucidate the molecular and cellular mechanisms of PD-1 as well as other co-receptors in the regulation of immune responses against self, cancer, and pathogen-derived antigens.
In addition to PD-1, we are focusing on LAG-3 because we have identified a loss-of-function mutation in LAG-3 gene exacerbates autoimmune symptoms of PD-1 deficient mice. LAG-3 is structurally similar to CD4 and has been reported to inhibit T cell activation. However, the molecular mechanisms of LAG-3-dependent inhibition remain ill defined. LAG-3 has been assumed to inhibit T cell activation by outcompeting CD4 for MHC class II binding. However, there are controversial reports and its function remained perplexing. Recently, we found that LAG-3 and CD4 do not compete each other for MHC class II binding. We also found that LAG-3 does not recognize MHC class II universally but recognizes MHC class II in a structural conformation-dependent manner. This is the first evidence of the target selectivity by an inhibitory co-receptor as its intrinsic property.
Many genetic and environmental factors are known to affect the development and the progression of autoimmune diseases. Although the function of individual genes in immune system has been extensively analyzed, it is largely unknown which genes are really involved and how multiple genes collaborate in the regulation of autoimmune diseases. We are trying to identify autoimmune susceptible genes comprehensively by genetically dissecting autoimmune susceptible mice and elucidate their synergistic function in the development of autoimmune diseases. Mice deficient for PD-1 gene develop different types of autoimmune diseases in different genetic background, suggesting that PD-1 deficiency exaggerates autoimmune susceptibility of strains. We are taking the advantage of PD-1 deficient mice to facilitate the identification of the autoimmune susceptible genes.
In addition to these basic researches, we are trying to develop new methods to cure cancers, autoimmune diseases, or infectious diseases by strengthening or weakening immune responses.
To roughly know our research, please read the following articles.
1. Sugiura D, Maruhashi T, Okazaki IM, Shimizu K, Maeda TK, Takemoto T, and Okazaki T.
Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses.
Science, 364(6440): 558-566, 2019
2. Shimizu K, Sugiura D, Okazaki IM, Maruhashi T, Takegami Y, Cheng C, Ozaki S, and Okazaki T.
PD-1 imposes qualitative control of cellular transcriptomes in response to T cell activation.
Molecular Cell, 77(5):937-950, 2020
3. Maruhashi T, Sugiura D, Okazaki IM, Shimizu K, Maeda TK, Ikubo J, Yoshikawa H, Maenaka K, Ishimaru N, Kosako H, Takemoto T, and Okazaki T.
Binding of LAG-3 to stable peptide-MHCII limits T cell function and suppresses autoimmunity and anti-cancer immunity.
Immunity, 55(5):912-924.e8, 2022
4. Sugiura D, Shimizu K, Maruhashi T, Okazaki IM, and Okazaki T.
T cell-intrinsic and -extrinsic regulation of PD-1 function.
International Immunology, 33(12):693-698, 2021
5. Maruhashi T, Sugiura D, Okazaki IM, and Okazaki T.
LAG-3: from molecular functions to clinical applications.
Journal of Immunotherapy of Cancer, 8(2):e001014, 2020