Regulatory T cells: molecular requirements for their selection and therapeutic use in autoimmune disease

Abstract

Regulatory T cells (Tregs), expressing the transcription factor Foxp3, form a key component of peripheral immune tolerance, guarding against auto-aggressive immune responses. Multiple Sclerosis is an inflammatory and demyelinating disease of the central nervous system (CNS) which is largely believed to be mediated by immune components reacting to the self myelin antigens that insulate the nerve fibres. Recent investigations have reported that regulatory T cells are dysfunctional in MS patients; therefore enhancing the regulatory T cell responses in MS is an attractive therapeutic target. Using the mouse model of MS, experimental autoimmune encephalomyelitis (EAE) we have attempted to develop disease-relevant Treg-based therapies to prevent disease induction. This required an understanding of the antigenic-reactivity of Tregs during disease. Results described in this thesis show that a proportion of Tregs in the draining lymph nodes and CNS were reactive to the disease initiating antigen(s) and could suppress in vitro responses of naïve T cells bearing transgenic T cell receptors, recognising the same antigen. Adoptive transfer of antigen-reactive Tregs suppressed disease induced with the same antigen, but also reduced disease induced with a distinct myelin antigen. Peptide-based tolerance using a high affinity MHC binding peptide analogue expanded and maintained antigen-reactive T cells which were tolerant to antigenic restimulation, although these cells did not express Foxp3. Peptide-treated mice showed reduced incidence of disease relapses during EAE induced against a distinct myelin antigen. Thus, while EAE and MS will involve a polyclonal effector T cell response to many antigens, therapeutic targeting of Tregs reactive against one CNS component may be sufficient to reduce disease. Endogenous expression of myelin autoantigen did not grossly alter the response of antigenreactive Tregs in the periphery. However, expression of endogenously derived viral superantigen enhanced the proportion of superantigen-reactive Foxp3+ Tregs in the periphery. This observation was extended using exogenous superantigen, suggesting that prolonged exposure to low dose (super)antigen tips the balance of the immune system in favour of regulation. This has implications for the ability to successfully fight infection, as well as for the limitation of autoaggressive responses and may contribute to the understanding of the hygiene hypothesis.