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Signal Network

Our Research

T cells play a central role in the promotion of the effector and regulatory functions in the immunological surveillance system, and aberrations of these functions can lead to various immunological disorders. Cytokines are critical factors in the transmission of information from the receptor to the nucleus as well as in the generation of communication networks among cells. Thus, the Cytokines secreted from T cells directly promote the effector and regulatory functions of T cells.
The main scientific goal of our laboratory is to understand the molecular basis of epigenetical regulation of effector cytokine locus and signal transduction cascades through cytokine signaling that regulate effector cytokine expression T cell differentiation. We are interested in how expression of Il4 and Il13 cytokine genes are independently controlled among various cell lineages including lymphoid and myriad lineages. Research activities are focused on the biochemical mechanisms of cytokine pathways and the lineage specific transcriptional regulation in Th2 cytokine gene expression.


Regulation of cis-acting elements of Il4 locus among different lineages producing IL-4 and IL-13



In order to understand epigenetic changes in chromatin structure at the T helper (Th2) locus correlate with IL-4 and IL-13 expression, we established series of a reporter transgenic mice and deletion of cis-acting elements from mouse genome. We recently demonstrated that conserved non-coding sequence-2 (CNS-2), located downstream of the Il4 locus is constitutively active enhancer in NKT cells as well as in a subset of CD44hi memory phenotype CD4+ T cells. In the study of T cell specific RBP-J deficient mice that lacks Notch signal, Th2 differentiation was selectively impaired. T cell specific RBP-J deficient mice showed abrogation of the CNS-2 enhancer activity and initial IL-4 expression in NKT and memory phenotype CD4+ T cells, and CNS-2 enhancer deficient mice resulted in a loss of initial IL-4 expression in NKT and memory phenotype CD4 T cells and Th2 differentiation in neutral condition. Therefore, major role of Notch signal is to regulate CNS-2 enhancer activity in NKT and memory phenotype CD4 T cells. This result also shows a functional significance of memory phenotype T cells for facilitating Th2 mediated allergic responses. Th2 cytokines, such as IL-4 and IL-13 are expressed in distinct lineages of cells that develop in different tissue environments. Several cell types have been reported to secrete IL-4 and IL-13, including CD4 T cells, Th2 cells, NKT cells, mast cells, basophils, and eosinophils although considerable research emphasis has been placed on understanding the molecular basis of Il4 gene regulation in CD4 T cells. However, the mechanisms of Th2 cytokine gene regulation among the distinct lineages are unclear. Our reporter transgenic mice and deletion mutant mice of cis-acting elements on Il4 and Il13 locus would be beneficial tool to answer the question of whether Th2 cytokine genes are distinctively regulated in different lineages of cells. Our GFP reporter transgenic system indicated that the distinct enhancer elements regulated transcription of the Il4 gene in distinct lineages of cells, and therefore this system would be useful tool to visualize the behavior of Th2 cells, memory T cells, NKT cells, mast cells, and basophils in various inflammatory site and lymph node.


Role of suppressor of cytokine signaling (SOCS) in immune regulation

The cytokine environment at the site of the initial antigen stimulation determines the direction of helper T cell differentiation into either Th1 or Th2 cells. The SOCS3 and SOCS5 proteins are implicated in this process to control the balance between Th1 and Th2 cells through the inhibition of IL-12 and IL-4 signaling pathway, respectively. Th2 environment accelerate the number of SOCS3 expressing CD4 T cells in allergic inflammatory site, subsequently enhancing the incident of allergic diseases including allergic conjunctivitis and atopic asthma. Therefore, the modification of SOCS3 and SOCS5 function and expression could be a target for therapeutic intervention to many aspects of allergic diseases.
The suppressors of cytokine signaling (SOCS) are a family of proteins that act to negatively regulate cytokine signaling. SOCS1 is a powerful negative regulator capable of inhibiting a wide range of cytokines through binding to all family members of the Jak family of tyrosine kinases via its SH2 domain. In order to understand how the abrogation of cytokine signaling by SOCS1 affects the development and maintenance of naive and memory CD4T cells, we investigated the generation of these cells in SOCS1 Tg mice. Cell surface phenotype analysis confirmed that most peripheral CD4 T cells in SOCS1 Tg mice had a memory phenotype even in a DO11.10 TCR transgenic or cd28 deficient background. Adoptive transfer of CD44lo CD4 thymocytes from SOCS1Tg mice again resulted in the development of CD44hi CD4 T cells. Our results suggest that IL-7 mediated STAT5 activation is essential for long term survival of naive CD4 cells after export from thymus, but that another SOCS1-sensitive cytokine is critical for short term naive T cell survival.
We have demonstrated that the SOCS family proteins are implicated in many aspect of acquired immunity through a control of the balance between Th1 and Th2 cells. We recently demonstrate that modification of Th1 response by SOCS5 expression in T cells augments innate immunity during septic peritonitis induced by cercal ligation and puncture. In vitro bactericidal activities of macrophages and neutrophils were markedly augmented in SOCS5 transgenic mice. These findings address the evidences that intervention of SOCS5 expression in T cells affects innate immunity and provide us new insight to investigate a cross-talk between innate and acquired immunity.