of the Max - MDC

Cellular Immunology of
Autoimmune Reactions –
Controlling the Balance between
Effector and Suppressor T Cells
Kirsten Falk and
Olaf Rötzschke
Direction and strength of the immune response is largely controlled by the equilibrium between effector and
suppressor T cells. While effector T cells drive proinflammatory reactions to eradicate pathogens and transformed
cells, suppressor T cells prevent autoimmune reactions and collateral damage by keeping the effector cells in
check. It is now generally accepted that regulatory T cells (Treg) are a key suppressor population responsible for
the maintenance of peripheral tolerance. They are a subset of CD4+ T cells that neutralises effector cells, such as
CD4+ effector T cells, by ‘bystander’ mechanisms. These bystander mechanisms are based on cell/cell contact or the
release of suppressive cytokines (e.g. TGF-b or IL-10) and do not require direct recognition of the affected effector
cell. Characteristic marker of Treg cells is the transcription factor Foxp3. It largely controls phenotype and function
and mutations in the Foxp3 gene can result in IPEX (‘Immune dysregulation, Polyendocrinopathy, Enteropathy X-
linked syndrome’), a severe and rapidly fatal autoimmune disorder characterized by the development of overwhelming
systemic autoimmunity. Specific aims of the group is to understand the subset composition and function of
Treg subset and to influence the balance between Treg and CD4+ effector T cells for immune interventions in autoimmune
diseases and cancer.
Recruitment of Treg cells by repeat antigens
Cooperation with R. Liblau, Toulouse, France and the
SFB650, Berlin
The rediscovery of suppressor cells offers a novel perspective
for the treatment of autoimmune diseases. Treg cells
inhibit effector cells only after activation by their antigenspecific
T cell receptor (TCR). The bystander mechanisms
triggered by this event result in a suppression of all effector
cells located in proximal vicinity to the Treg cell.
Recruitment of these cells with a single antigen expressed
by the damaged tissue therefore allows in principle to
induce dominant protection from the autoimmune attacks.
In various experimental animal models of autoimmune diseases
we have demonstrated that repeat antigens consisting
of linear copies of the T cell epitope are particularly
effective to induce tolerance. Mice treated with multimerized
antigens of the myelin sheath did no longer show the
symptoms of experimental autoimmune encephalomyelitis
(EAE), a multiple sclerosis-like autoimmune disease (MS)
caused by the destruction of the myelin sheath. In another
animal model of type I diabetes we could show that the protection
was in fact achieved by the antigen-specific recruitment
of Treg cells. Naive mice vaccinated with repeat model
antigen expressed by the insulin producing islet cells were
able to protect the tissue from the attacks of activated TH-1
effector cells expressing a transgenic T cell receptor specific
for the model antigen. Transfer of these TH-1 cells into nonvaccinated
controls leads to the induction of diabetes within
less than 5 days. Thus, repeat antigens induce ‘active’
tolerance by the activation of dominant suppressor cells
conferring tissue-specific protection from immune attacks.
Recent studies by the group suggest that the strategy is also
widely used by parasites such as plasmodium spec.
Recruitment of Treg cells to induce active tolerance therefore
appears to be a particularly effective way to mediate
immune evasion. A focal point of the current research is
therefore to explore the underlying molecular and cellular
mechanisms of tolerance induction and to develop the concept
of repeat antigens into future therapies of autoimmune
diseases and transplantations.
Regulatory effector/memory-like Treg cells (T REM )
Cooperation with G. Borsellino/L.Battisitini, Rome, Italy
and the GRK 1258, Berlin
Analogue to conventional CD4+ effector T cells, also Treg
cells are divided into naive cells and antigen experienced
memory-type cells. While the equivalent of long-lasting
‘central-memory T cells’ has not been found, at least ‘regulatory
effector/memory-like’ Treg cells (T REM ) could be clearly
identified. As ‘short-term memory’ they are crucial to
contain proinflammatory responses inside the inflamed tissue.
They act as important counter players of CD4+ effector/memory
T cells (T EM ) and accumulate in the central nervous
system during autoimmune inflammation but also in
tumour infiltrates were they may prevent effective tumour
rejection. For experimental autoimmune encephalomyelitis
140 Cancer Research