Role of regulatory T cells in immune tolerance

In this present work, we investigated the role of dendritic cells (DC) and
regulatory T cells (Treg) in immune tolerance as well as their potential in the
treatment of autoimmune or graft versus host (GvH) diseases.
In the first study, we show that double transgenic mice expressing influenza
hemagglutinin (HA) under the control of the CD11c promoter and a T cell
receptor (TCR) specific for HA develop systemic auto-immunity and die
prematurely. In double transgenic mice, negative selection of the transgenic
TCR expressing T cells in the thymus is practically complete, however
significant number of activated T cells expressing the TCR clonotype can be
found in the periphery. By breeding double transgenic mice on a rag2-
deficient background, we could demonstrate that T cells escape negative
selection by expression of an endogenous TCR α chain.
In clear contrast, our collaborators demonstrated that expression of HA under
the control of the medullary thymic epithelial cell (mTEC)-specific autoimmune
regulator (AIRE) promoter together with HA-specific TCR, results in the
development of HA-specific naturally occurring Treg (NTreg) cells. AIRE-HA x
TCR-HA are healthy and absolutely tolerant to HA. Altogether, these data
strongly suggest that the outcome of antigen encounter in the thymus or the
periphery critically depends on the identity of the antigen presenting cells.
In addition, we analysed the potential of transferred HA-specific Treg cells to
interfere with spontaneous autoimmunity in CD11c-HA x TCR-HA double
transgenic mice. We conclude that transfer of HA-specific Treg into newborns
rescues double transgenic mice from early death but does not prevent or
delay the onset of the systemic autoimmunity.
In a second study, we showed that fms-like tyrosine kinase ligand (FLT3L)
treatment, already known to increase DC number, indirectly leads to
expansion of peripheral NTreg. The increased number of NTreg is due to
proliferation of pre-existing NTreg, likely due to favoured interactions with the
increased number of DC. We investigated the therapeutic potential of FLT3L
and could show that FLT3L treatment had no effect on normal immune
response but could prevent death induced by acute GvHD. These data reenforce
the relevancy of FLT3L treatment in transplantation or autoimmune
settings by its ability to increase both the number of immature tolerizing DC
and NTreg.
Finally, in addition to immune tolerance, we investigated the so-called
phenomenon of auto-reconstitution already known since a long time.
We generated bone marrow (BM) chimeras by reconstituting lethally irradiated
C57BL/6 mice with either syngeneic rag2-deficient or CD3ε-deficient BM
neither of which is capable of generating T cells. We show that in the absence
of donor-derived thymopoiesis, host-derived T cells can reconstitute 35% of
the normal T cell pool. By comparing thymectomized versus nonthymectomized
host, we show that host-derived T cells, comprised a major
subpopulation of de novo generated, thymus-derived, polyclonal cells. Host-
derived thymocytes regenerated from conventional DN1-2 prothymocytes and
their differentiation recapitulated normal thymic ontogeny. Thus, host-derived
T cells might provide a first line of defence against infections during recovery
from lymphopenia after BMT. This conclusion is supported by the fact that
host-derived T cells were fully functional.