Regulatory and Effector Immune Cells in a Spontaneous Multiple Sclerosis Model

Abstract

Multiple sclerosis (MS) affects around 2.5 million people worldwide, making it one of the most common neurological conditions in young adults. Experimental autoimmune encephalomyelitis (EAE) has been the standard animal model for MS where antigens are introduced alongside powerful T cell polarising adjuvants to induce disease. This general protocol has been both helpful and sometimes limiting in modelling T cell events as the immune adjuvants make interpretation of mechanism more difficult. There is a need for more relevant mouse models lacking the inherent biases of immune adjuvants and providing a human context for disease initiation and progression. For this thesis, I have characterized the disease and cellular dynamics in a humanized, T cell receptor (TCR) transgenic mouse model, termed Line7. The mice develop spontaneous, ascending paralysis. T cell responses defined in these transgenics have direct relevance to the human setting since they are by definition HLA-­‐DR15 restricted and are allowed to progress without interference from modifying adjuvants. I have focused on the dynamics of Th1 and Th17 cells in both the initiation and progressive phase of disease and the role that regulatory T cells play in affecting this balance. Initial observation of naturally progressing disease showed that in this model IFNγ+ cells dominate through disease initiation and IL-­‐17+ cells are only observed in the affected tissue once disease is established. The cytokine milieu favours Treg differentiation over Th17 cells and regulatory T cells accumulate in the central nervous system (CNS) but are ineffective at halting progression or initiating recovery. Through removal of the Tregs, severe acceleration of symptoms developed with uncontrolled infiltration of lymphocytes into the CNS. IFNγ production by CD4 and CD8 cells is upregulated at the expense of IL-­‐17 but reconstitution of the Treg population halts disease progression, illustrating the roles of Tregs in regulating autoreactive T cell activity and controlling cellular infiltration across immunological barriers. Therefore the use of this model, without the introduced biases of immune adjuvants, has highlighted the importance of the Th1/Treg balance in disease initiation over Th17 cells whilst underlining the critical role for Tregs in preventing autoimmune conditions or halting ongoing disease even in highly susceptible individuals.