in vivo

Research Unit for
Immune Homeostasis
small subpopulation of T lymphocytes
A known as regulatory T cells (T reg
) plays a
central role in preventing pathological immune
responses such as autoimmunity, inflammation
and allergy, and thus ensures dominant tolerance
to self and innocuous environmental antigens.
This has been well illustrated by our previous
finding that the development and function of T reg
is controlled by the transcription factor Foxp3,
whose deficiency leads to the development of
a fatal autoimmune pathology in a spontaneous
mouse mutant strain called scurfy and in human
patients with the IPEX syndrome.
The identification of Foxp3 as the “master
regulator” of T reg differentiation and function has
provided a key to a number of outstanding and
as yet unresolved questions concerning the role
T reg cells in tolerance and immune regulation,
and the physiology of these cells including
their origins, the mechanisms controlling their
development and function, and their antigen
specificity. Resolving these issues is the goal of
this laboratory.
Unit leader
Shohei Hori
Research Scientist : Takeshi Nishikawa
Technical Staff
Student Trainee
: Takahisa Miyao
Ying Wang
: Noriko Komatsu (JRA)
In vivo function of T reg in tolerance and
immune regulation
Since both scurfy and Foxp3-deficient
mice fail to generate T reg , it is now believed
that a T reg deficiency is the primary cause of the
immune dysregulation in Foxp3-mutant mice
and humans. It has also been proposed that
Foxp3 inactivation in non-hematopoietic tissues,
particularly in thymic epithelium, is required for
pathogenesis, since scurfy bone marrow cells
fail to transmit the disease to lethally irradiated
wild-type hosts. To determine the relative
contributions of these two proposed pathways
to the autoimmune pathology in scurfy mice,
we repeated this radiation chimera experiment
and found that the lack of pathology is due to
the presence of radioresistant endogenous
Foxp3 + T reg of the host. In addition, chimeras
carrying the scurfy mutation only in nonhematopoietic
cells had no evidence of
autoimmune pathology. Thus, Foxp3 deficiency
in non-hematopoietic cells does not contribute
to the scurfy disease. Furthermore, our analyses
of radiation chimeras revealed that the peripheral
T reg pool is fully and specifically restored and
maintained by radioresistant endogenous T reg or
adoptively transferred exogenous T reg through
“homeostatic” proliferation in the absence of
T reg production from scurfy donor bone marrow
cells. These results thus provide evidence that
60