Yamasaki Lab／Division of Host Defense Department of Molecular Immunology
Our bodies are continuously exposed to external and internal insults caused by infection and tissue damage, most of which are primarily sensed by immune receptors to maintain tissue homeostasis. However, the molecular mechanism by which these receptors discriminate diverse insults to elicit suitable immune responses remains elusive. We have found that C-type lectin receptors can sense both damaged self and non-self pathogens (Figure 1). Recently, we also showed that clustered C-type lectin receptors, Mincle, MCL, Dectin-2 and DCAR, can recognize mycobacteria through their unique glycolipids possessing adjuvant activity (Figure 2). Our objective is to illustrate the principle behind the regulation of immune responses through C-type lectin receptors in physiological and pathological settings. Based on these results, we also aim to design new methods to efficiently elicit or modulate immune responses.
To this end, our research is focusing on the following axes:
1) Immune sensing of pathogens and damaged-self via C-type lectin receptors.
2) Unique T cell responses induced by self peptides.
3) Atypical T cell subsets critical for autoimmune diseases.
C-type lectin receptors (CLRs) sense both “non-self pathogens” and “damaged self”.
CLRs are involved in innate immunity; however, this family exhibits higher diversity and ligand specificity than other innate immune receptor families such as Toll-like receptors due to the wider variety of genes [Fig.1]. CLRs recognize pathogen-associated molecular patterns. We showed that Mincle (macrophage-inducible C-type lectin) recognizes the glycolipid TDM (trehalose-6,6'-dimycolate), a component of the Mycobacterium tuberculosis cell wall. This CLR acts as a sensor to trigger the immune response through a signaling pathway that involves FcRγ and CARD9, among other components. We also identified the ligands through which the CLRs MCL (macrophage C-type lectin), Dectin-2 (dendritic cell-associated C-type lectin-2), and DCAR (dendritic cell immunoactivating receptor) recognize M. tuberculosis and other pathogens, and elucidated some of the mechanisms by which they induce immune responses.
In addition, in a recent study, our group shed light on the function of Mincle in the recognition of endogenous ligands. Mincle can bind to β-glucosylceramide, a glycolipid that is released by host cells after damage. Thus, Mincle not only detects pathogens or foreign ligands, but also endogenous molecules released by damaged cells to activate the immune system and the response to “danger” situations.
We are presently investigating in further detail the recognition of both self and non-self ligands by this family of receptors and their role in immunity [Fig.2].
Self ligands are recognized by T cell receptors (TCRs) and play an important role in T cell persistence
T cells pass various selections of their TCRs before they are released from the thymus into the periphery. TCRs that weakly bind to self ligands cause T cell retention, and the signaling cascades induced by self ligands are important for T cell persistence but do not lead to T cell activation. Our objective is to clarify the recognition of “self” by TCRs and the distinct signals transduced by the same TCR upon stimulation with self and non-self ligands.
Novel T cell subsets contribute to autoimmune diseases
Recent evidence has shown that novel T cell subsets are responsible for autoimmune phenotypes that are comparable with human disorders. We are interested in the ligands that are recognized by these pathogenic T cells and the mechanisms via which the diseases develop. Based on the analysis of the corresponding subsets in human, we aim to design new methods to diagnose and treat autoimmune diseases.
- Prof.: Sho Yamasaki
- Asst. Prof. : Masamichi Nagae
- Asst. Prof. : Eri Ishikawa
- Postdoc. : Takashi Shimizu
- Postdoc. : Minori Asa
- (1) The kinetics of signaling through the common FcRγ chain determine cytokine profiles in dendritic cells. Watanabe M., et al. Sci. Signal. (2023) 16:eabn9909
(2) Direct activation of microglia by β-glucosylceramide causes phagocytosis of neurons that exacerbates Gaucher disease. Shimizu T., et al. Immunity. (2023) 56:307-19
(3) Human Dectin-1 is O-glycosylated and serves as a ligand for C-type lectin receptor CLEC-2. Haji S., et al. eLife. (2022) 11:e83037
(4) Symbiotic bacteria-dependent expansion of MR1-reactive T cells causes autoimmunity in the absence of Bcl11b. Shibata K, et al. Nat. Commun. (2022) 13:6948
(5) Identification of conserved SARS-CoV-2 spike epitopes that expand public cTfh clonotypes in mild COVID-19 patients. Lu X, et al. J. Exp. Med. (2021) 218:e20211327
(6) Helicobacter pylori metabolites exacerbate gastritis through C-type lectin receptors. Nagata M., et al. J. Exp. Med. (2021) 218:e20200815
(7) Lipoteichoic acid anchor triggers Mincle to drive protective immunity against invasive group A Streptococcus infection. Imai T., et al. Proc. Natl. Acad. Sci USA. (2018) 115:E10662-71
(8) Intracellular metabolite β－glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity. Nagata M., et al. Proc. Natl. Acad. Sci. USA. (2017) 114:E3285-94
(9) Protein kinase D regulates positive selection of CD4(+) thymocytes through phosphorylation of SHP-1. Ishikawa E., et al. Nat. Commun. (2016) 7:12756
(10) C-type Iectin receptor DCAR recognizes mycobacterial phosphatidyl-inositol mannosides to promote a Th1 response during infection. Toyonaga K., et al. Immunity. (2016) 45:1245-57
- Yamasaki Lab