in vivo

Laboratory for Signal Network
cells play a central role in the effector and
T regulatory functions in immunologi cal
surveillance, and aberrations of these functions
can lead to various immunological disorders.
T helper 1 (Th1) cells secrete IL-2, IFN-γ and
TNF-α in cellular immune responses against
intracellular pathogens and viruses. By contrast,
Th2 cells produce IL-4, IL-5, IL-6, IL-10 and IL-13
in humoral immune responses, mainly against
extracellular pathogens, and also account for
allergic immune responses. Recently, a new
subset of Th cells, Th17, has been characterized
based on IL-17 production. Th17 cells are
associated with many aspects of autoimmune
tissue inflammation. Cytokines are critical
mediators of the transmission of information from
the cytokine recep tor to the nucleus as well as
in the communication between cells. Thus, the
cytokines secreted from effector helper T cells
play a critical role in controlling the outcome of
immunologi cal surveillance. The overriding goal
of our laboratory is to understand the molecular
basis of helper T cell differentiation.
Alternative regulation of Th2 cytokines in
Th1 cells.
Team leader
Masato Kubo
Research Scientist
Special Postdoctoral Researcher
Technical Staff
Student Trainees
Assistant
: Mariko Okamoto
: Shinya Tanaka
: Yukiko Matsuno
Yoshie Suz uki
Maiko Natsume
: Yasutaka Motomura
(Junior Research Associate)
Hiroko Suyama
Emi Ohkubo
: Michiko Nakamura
During the last two decades, it has become
dogma that theTh1 and Th2 cytokine profiles
are strictly conserved and immutable during T
cell differentiation. Among the signature Th2
cytokines, IL-4 and IL-13 expression is thought
to be controlled by common transcriptional
mechanisms. However, we found that chronic
antigenic stimulation could preferentially
alter the cytokine profile of Th1 cells to elicit
significant IL-13, but not IL-4, expression in both
mouse and human systems. We designated
these IL-13 producing Th1 cells as Th1/13
cells. IL-13 expression is tightly associated
with the expression of a putative clockcontrolled
transcriptional factor, E4BP4, and
individual Th1/13 cells from mouse and human
consistently co-expressed E4BP4, IFN-γ, and
IL-13. The promoter region of the Il13 locus was
constitutively transcriptional accessible, and the
binding of the induced E4BP4 to the promoter
resulted in IL-13 expression by conventional
Th1 cells. Therefore, E4BP4 is a critical regulator
for the expression of IL-13 in Th1/13 cells and for
activating this normally silent gene in Th1 cells.
Th1/13 cells were found in human asthmatic
patients who had a less Th2 biased phenotype,
and the administration of Th1/13 cells in a
mouse asthma model resulted in induction of
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