in vivo

eosinophil-mediated asthma responses. These
results indicate that E4BP4 controls the induction
of a unique T subset, Th1/13, to possibly initiate
allergic incidents in otherwise chronic Th1
biased situations. Our findings provide a novel
insight into the traditional dogma of Th1 and
Th2 balance in allergic diseases.
Identification of the molecular basis of
Th2 bias
Genetic background is known to influence
the type of immune responses, and the
molecular basis of TH2 bias has been a longstanding
mystery in the field of immunology.
Genetic linkage analyses have been used in a
comparison of BALB/c versus B10.D2 strains
with respect to their ability to produce IL-4
upon initial TCR stimulation. These studies
have identified Determinant of IL-4 commitment
(Dice)1.2 on chromosome16 as one trait locus
that controls Th2 bias . We found that Mycinduced
nuclear antigen with a molecular mass
of 53kDa (mina53)expression was consistently
higher in Th1- prone strains (B10.D2) than Th2-
prone strains (BALB/c). The genome sequences
of the 5’ flanking sequence and the first intron
region contained multiple SNPs among different
mouse strains, and these tightly associate with
the propensity to produce initial IL-4. Interestingly,
The SNPs in the promoter region of human
mina53 gene associated with severity of allergic
asthma. These results indicated that Mina53 is
a useful genetic maker for Th2 bias and allergic
predisposition in mouse and human.
Role of memory phenotype CD4 T cells in
Th17 mediated immune-regulation
The distal 3’ enhancer in the Il4 locus
corresponds to a highly conserved region termed
conserved non-coding sequences (CNS)-2.
Using a transgenic GFP reporter system,
we demonstrated that the CNS-2 enhancer
regulated the initial expression of IL-4 in CD44 hi
memory phenotype (MP) CD4 T cells. These
IL-4 producing MP-CD4 cells co-expressed
IFN-γ, while GFP - IL-4 non-producing MP cells
expressed robust IL-17 and IFN-γ. The IL-17
producing MP (MP-Th17) cells appeared to be
distinct population from canonical Th17 cells
since MP-Th17 cells developed in the absence
of IL-6, which is required for Th17 differentiation.
The MP-Th17 cells had an alternative role to
induce IL-17 production by dendritic cells (DC)
in an IL-17 dependent manner. These results
demonstrated that rapid IL-17 production by
MP-Th17 cell resulted in the secondary
production of this cytokine by DCs to exacerbate
inflammatory responses.
Recent publications
Seki, Y., Yang, J., Okamoto,
M., Tanaka, S., Goizuka, Farrar,
M.A., R., and Kubo, M., ; The
role of IL-7/STAT5 pathway and
suppressor of cytokine signaling
1 in maintenance of naive and
memory CD4 T cells in peripheral
lymphoid organs. J. Immunol.
1;178(1):262-70, 2007
Numata, K., Kubo, M., Watanabe,
H., Takagi, K., Mizuta, H., Okada,
S., Ito, T., and Matsukawa, A.,;
Overexpression of Suppressor
of Cytokine Signaling-3 in T cells
Exacerbates Acetaminophen–
induced Hepatotoxicity. J. Immunol.
178 3777-3785, 2007
Yoshimura, A., Naka, T., Kubo, M.,;
SOCS proteins, cytokine signalling
and immune regulation. Nature
Review Immunology 7, 454-465,
2007
Yagi, R., Tanaka, S., Motomura, Y.,
and Kubo, M., The regulation of Il4
gene expression in mast cells and
basophils is regulated by distinct
proximal and distal 3’ enhancers.
Mol. Cell. Biol. 27(23), 8087-8097,
2007
Kano, S., Sato, K., Morishita,
Y., Vollstedt, S., Kim, S., Taki,
S., Honda, K., Kubo, M., &
Taniguchi, T.; Regulation of Th1
vs. Th17 differentiation: Selective
contribution of thetranscription
factor IRF1 to the IFN-γ-IL-12 axis
of signaling networks in CD4 + T
cells. Nature Immunology 9, 34 -
41, 2008
Figure
Chronic antigen stimulation induced E4BP4 mediated IL-13 production
Significant IL-13 expression could be induced in mouse Th1 cells following chronic antigenic stimulation. This
chronic stimulation initiated expression of E4BP4, leading to IL-13 expression in conventional Th1 cells. The
IL-13 producing Th1 cells were found among human T cells from asthmatic patients. IL-13 produced by Th1
cells induced an eosinophil mediated asthmatic response in a mouse asthma model.
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