Regulatory T cells expressing the transcription factor Foxp3 have a critical role in the
maintenance of tolerance to both self and innocuous exogenous antigens. Humans and mice
die from overwhelming autoimmunity in the absence of Foxp3+ Treg whilst administration
of regulatory T cells has shown promise therapeutically in ameliorating autoimmunity in
several animal models. Regulatory T cells arise naturally in the thymus (nTreg) but may
also be induced from naïve Foxp3- cells in the presence of TGF-β (iTreg), both in vitro and
in vivo. This thesis focuses on in vitro generated mouse iTreg, testing the hypothesis that
they are able to effect bystander suppression; iTreg activated by a given antigen are able to
suppress other responding cells with different antigen reactivities.
Chapter 3 details an in vitro assay system using iTreg and responder cells recognising
different antigens (TCR transgenic cells). Evidence for bystander suppression is presented
and that did not require the presence of iTreg-relevant antigen but did require iTreg-relevant
MHC Class II. The kinetics of iTreg suppression are discussed, with evidence presented that
iTreg exert their effects early in co-culture. Chapter 4 identifies the production of three pro-inflammatory
cytokines by iTreg - IFN-γ, GM-CSF, and TNF. These were not involved in
the in vitro suppressive mechanism, but early abrogation of TGF-β signalling did inhibit
suppression. Chapter 5 describes the in vivo function of iTreg under various experimental
protocols. iTreg did not limit initial proliferation of naïve T cells in response to antigen but
did limit the development of effector cells producing pro-inflammatory cytokines. Exposure
to a pro-inflammatory environment in vivo led to iTreg producing IFN-γ and TNF, but not
GM-CSF. This could be replicated in vitro by exposure to IL-6, IL-12 or IL-27. Finally,
evidence for bystander suppression by iTreg in vivo is presented, with a reduction in effector
cells producing pro-inflammatory cytokines shown in an allergic airways diease model
