Controlling Autoreactivity of CD4 T Cells by Local Tolerance Induction
Controlling Autoreactivity of CD4 T Cells by Local Tolerance Induction
IRMGARD F(RSTER 0
0 alnstitute for Genetics, University of Cologne , Cologne , Germany
*Corresponding author. Present address: Institut ftir Genetik, Weyertal 121, D-50931 K61n, Germany.
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INTRODUCTION
Autoimmune diseases are often caused by the
inappropriate activation of CD4 T cells specific for
peripheral self-antigens. Since these cells recognize
their target antigens in the context of MHC class II
molecules on the surface of specialized
antigenpresenting cells (APC), the induction of immunity, or
alternatively tolerance, of CD4 T cells depends on
the release of antigens from peripheral tissues and
uptake by APC. To study this process, transgenic
mouse models have been established in which
experimental self-antigens are expressed under the
control of tissue-specific promoters. With the
availability of T-cell-receptor (TCR)-transgenic mice
specific for the respective antigen, the T-cell response
toward such neo self-antigens can be followed
directly during the development of the immune
system (for review, see Himmerling et al., 1993;
Kruisbeek and Amsen, 1996; Mondino et al., 1996)
The transgenic mouse model described here has
been originally established by D. Hanahan with the
intention to study tissue-specific tumorigenesis
following expression of a viral oncogene, the SV40 T
antigen (Tag), under control of the rat insulin II gene
promoter (RIP)
(Hanahan, 1985)
. Independent lines
of RIP-Tag transgenic mice were later shown to
mount characteristic immune responses toward Tag,
depending on the onset and level of Tag expression
during ontogeny
(Adams et al., 1987)
. Thus,
RIP1Tag2 (abbreviated RT2) mice with embryonic onset
of Tag expression were found to establish systemic
tolerance toward Tag, whereas other lines of mice
with delayed onset of Tag expression developed a
spontaneous autoimmune response against their
pancreatic/3 cells (
Skowronski et al., 1990
; Jolicoeur et
al., 1994;
F6rster et al., 1995
).
With the aim of generating Tag-specific
TCRtransgenic mice to study the mechanism of induction
of tolerance versus autoimmunity in this system, we
identified and cloned a MHC class II restricted
Tagspecific TCR that was expressed on Tag-specific
CD4 T cells isolated from pancreatic infiltrates of an
autoimmune RIP1-Tag5 mouse (
F6rster et al., 1995
).
Genomic constructs encoding this Tag-specific TCR
were injected into fertilized mouse oocytes and two
independent lines of transgenic mice were obtained in
which either a single copy of the TCR c-chain gene
and two copies of the TCR/3-chain gene (TCR1 mice)
or multiple copies of both TCR c and/3 (TCR2 mice)
were cointegrated into the genome. With the help of
an anti-idiotypic antibody specific for the transgenic
TCR, it could be demonstrated that TCR1 mice
expressed the transgenic receptor on no more than
0.5% of thymocytes and 10% of peripheral CD4 T
cells, whereas the majority of peripheral T cells
expressed endogenous TCR. In contrast, TCR2 mice
carried the transgenic TCR on almost all thymocytes
and 90% of peripheral T cells (
F6rster et al., 1995
).
The reason for this differential expression of the
transgenic TCR in TCR1 versus TCR2 mice is
presently unknown but most likely depends on
position effects of the transgene integration site.
ESTABLISHMENT OF PERIPHERAL
TOLERANCE DEPENDS ON THE
FREQUENCY OF AUTOREACTIVE T CELLS
When the two different Tag-specific TCR-transgenic
lines were crossed to the tolerant RT2 line, we found
that only RT2/TCR1 mice established tolerance to
Tag, as evident by deletion of most of the transgenic
T cells and functional inactivation of the remaining
ones. In contrast, RT2/TCR2 double-transgenic mice
failed to develop peripheral T-cell tolerance. This
result could be attributed to the different frequencies
of autoreactive T cells in TCR1 versus TCR2 mice
rather than intrinsic differences between the two lines,
as demonstrated by two independent experimental
approaches. In the first series of experiments, the
frequency of Tag-specific T cells in TCR2 mice was
reduced by generation of mixed bone-marrow
chimaeras in which bone marrow derived from TCR2
mice was mixed at various ratios with bone marrow
from nontransgenic mice and transferred into
sublethally irradiated RT2 or negative control mice.
Analyzing the tolerance status of these chimaeras,
we could demonstrate that transgenic (Id+) T cells
derived from TCR2 mice were susceptible to
tolerance induction when present at low frequencies (i.e.,
less than 15% of peripheral CD4 T cells) (
F6rster et
al., 1995
). Conversely, in a different set of
experiments, the frequency of Id T cells in TCR1 mice was
increased to 100% by breeding of the TCR1 line into
the RAG-l-deficient background
(Mombaerts et al.,
1992)
. Interestingly, even in the absence of
endogenous TCR rearrangements, the absolute number of
transgenic T cells in TCR1/RAG-1 -/- mice remained
low, that is, the (...truncated)