Our research focuses are how constituents of innate immunity and adaptive immunity distinguish self from non-self entity and the cross-talk between the two arms (A, B). Further, we aim to elucidate the roles of immune cells in tumor micro-environmet (C). We aim at developing mouse models for human diseases caused by auto-reactive or hyper-reactive immune responses.(D)
A. Host-pathogen interaction/Innate immune signaling
This research topic is to elucidate molecular mechanisms by which innate immune system senses the invasion of host by pathogenic microorganisms, decodes the pattern associated with them, transforms it to an information signal(s), which triggers a signal cascade(s) that leads to activation of adaptive immune system. To reveal the intricate survival race between host and pathogen, and to contribute to the development of better therapeutic agents against intracellular pathogens, we are currently investigating molecular players and their functions in various innate immune signaling pathways triggered by Listeria, a model intracellular bacterial pathogen.
B. The interplay between myeloid cells and T cells
1. Tracking myeloid cell lineages and development in live animals
The immune response is mediated by numerous cell types and their effector molecules, and accompanied by inflammatory responses, which are featured by the infiltration of myeloid cells to the lesion. These infiltrating myeloid cells cooperate with T cells and other immune cells and play critical roles in many steps of immune response. They are comprised of many different subsets. However, their functional contribution in the physiological and pathological condition remains to be determined in live animals. Therefore, accurate identification of the cells that are responsible in whole animals is critical to target the culprits. Our lab is working on generating in vivo tools that allow us to track and delete monocytic myeloid subsets, determining their roles in various pathophysiologic conditions, and identifying the lineage determinants of various subtypes of monocytic myeloid cells.
2. Molecular mechanisms of the interplay between myeloid cells and T cells
T helper (Th) cells occupy a central position in orchestrating the diverse cell types that mediate host immunity to infections or tumors. T helper cells have been functionally classified into three major subtypes, Th1, Th2 and Th17, based on the types of immune molecules, called cytokines, that each subtype secretes. Th cell differentiation to each subset is determined by integration of communication between T cells and myeloid cells. Although many factors have been known to affect differentiation of Th1 and Th17, the initial cues for Th2 differentiation and the responsible myeloid cells remain unknown. We are investigating types of myeloid cells and molecular machinery involved in this process by tracing Th differentiation in cytokine reporter animals where the production of cytokines can be visualized in live animals.
C. Elucidation of the roles of immune cells in tumor microenvironment
Recently much attention has been paid to the association of inflammation with oncogenesis and tumor progression. We are studying the immune cells within the tumor micro-environment and their progenitor cells to reveal the cross-regulation between the tumor and immune cells, finding a key(s) to unlink them.
D. Development of mouse models for human immune-mediated diseases
Unregulated or excessive immune responses, called hypersensitivity, can cause tissue injury and diseases including allergy and asthma. The hypersensitive reaction due to the breakdown of tolerance is responsible for many diseases, the so-called autoimmune diseases, which request high medical and socioeconomical costs. Mouse models for autoimmune diseases have been highly valuable in identifying the underlying defects in the human diseases and understanding better the causal relations. Furthermore, they can be used as powerful preclinical models to devise new therapies and re-evaluate pre-existing and newly-developed therapies. Recently, new platforms of whole-genome sequencing provide genetic variations associated with various human diseases. However, the genes found in such genome-wide association studies await further validation of causal links to the diseases. In order to address this issue and to understand pathological mechanisms, we are developing mouse models that recapitulate the whole spectrum of disease manifestation shown in human autoimmune or immune-mediated diseases.