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Tokushima Bunri University
Kagawa School of Pharmaceutical Sciences

Research Themes:

 The mechanisms of immune cell trafficking and the regulation of immune responses are our main themes to clarify. Especially, we study roles of nuclear receptor ligands including vitamin A & D and various hormones in regulating immune functions especially in mucosal systems including the gut. By pursuing these biologically fundamental questions, we set a goal to establish a solid basis of new remedies and drug discovery for various diseases.
 

Recent Study:

  For efficient immune responses, immune cells with proper functions need to migrate into right sites in the body. T cells, known as the control tower of the immune system, patrol the whole body along with the blood vessels and lymphatic vessels. However, they cannot migrate into non-lymphoid tissues before they are activated with antigen in the secondary lymphoid organs. Once they are activated and become effector or memory T cells, however, they can migrate into non-lymphoid tissues. They tend to migrate into the tissue that is associated with the secondary lymphoid organ where they are activated. This type of migration is called “homing”. For example, T cells that are activated with antigen in the small intestine-relate secondary lymphoid organs, Peyer’s patches (PP) and mesenteric lymph nodes (MLN), tend to migrate into small intestinal tissues including the lamina propria. In 2004, we found that vitamin A-derived retinoic acid is the physiological factor that imprints gut-homing specificity on T cells. We also found that subpopulations of dendritic cells (DC) in PP and MLN express the key enzyme of retinoic acid synthesis, RALDH (retinaldehyde dehydrogenase), and are capable of producing retinoic acid from vitamin A (retinol). They imprint T cells with the gut-homing specificity by delivering retinoic acid to T cells during antigen presentation. In 2006, we also found that a similar mechanism is involved in the imprinting of B cells with gut-homing specificity by a collaboration mainly with Dr. von Andrian’s group and Dr. Adams’ group.

    In 2009, we established a method for estimating the enzyme activity of RALDH in each DC, and identified the retinoic acid-producing subpopulation in MLN-DC and PP-DC. The RALDH2 isoform was mostly responsible for the activity. Depending on these results, we searched for the physiological factors that induce RALDH2 expression in DC in the gut or in MLN. We found that GM-CSF (granulocyte-macrophage colony-stimulating factor) plays a major role in the induction, and that retinoic acid itself plays a role as an essential cofactor. IL-4 and IL-13 exhibited effects similar to those of GM-CSF on RALDH2 expression, but are found to be dispensable by the analysis of their receptor-deficient mice. The stimulation through Toll-like receptors enhanced the RALDH2 expression in DC as well as DC maturation.

    In 2007, it was reported by several groups that the retinoic acid-producing DC not only regulate lymphocyte trafficking but also enhance the differentiation of Foxp3+ inducible regulatory T cells (iTreg) and suppress that of pro-inflammatory Th17 cells. Indeed, GM-CSF-treated DC that express RALDH2 could enhance the differentiation of Foxp3+ iTreg and suppress that of Th17. Presently, we are analyzing the relationship of the regulation of immune responses by vitamin A levels and the risk of acquiring immunological diseases, the molecular mechanisms retinoic acid effects and RALDH2 expression, and the possibility of their disruption by environmental chemicals, and are searching for other regulators or “imprinters” of other homing specificities.


Legend of Figures

Left Panels: CD4+ naive T cells were activated with or without retinoic acid treatment, labeled with  green and red fluorophores, respectively, and were adoptively transferred into normal mice. The retinoic acid treated cells (Green) far more efficiently migrate into the Peyer’s patches and lamina propria of the small intestine than the untreated cells (Red) (Top). However, in the inguinal lymph node, a reverse tendency was observed (Bottom)

Right Panels: The distribution of CD4+ cells (Purple Red) and cell nuclei (Blue) was examined in the lamina propria of the small intestine in control mice (Top) and vitamin A-deficient mice (Bottom). From the lamina propria of the small intestine in vitamin A-deficient mice, almost all CD4+ T cells were depleted. (Data from “Iwata et al., Immunity 21:527-538, 2004” with the permission from Cell Press)