UC Irvine

Multiple sclerosis (MS) is a chronic, inflammatory disease characterized by focal demyelinated lesions in central nervous system (CNS) caused by infiltrating autoreactive T cells that target components of the myelin sheath. These autoimmune attacks result in demyelination and lead to axonal loss, which results in decreased neurological function. Patients suffering with MS can experience a wide range of symptoms including vision problems, muscle weakness, fatigue, and paralysis. Currently, more than 2.8 million people suffer from MS worldwide. Available therapeutics rely on disease modifying therapies (DMTs) which suppress the immune system to limit disease progression. Currently there are no available therapeutics for MS which restore or repair damage in the CNS caused by the immune system. Human Neural Stem Cell (hNSC) transplantation offers a promising approach to restoring function to patients by replacing or restoring damaged cells in the CNS. Recent studies using hNSC transplantation in mouse models of MS have revealed that despite being rejected, hNSC transplantation results in immune suppression and endogenous remyelination. However, it remains unclear how this remyelination response is generated. In Chapter 2, we present direct evidence that hNSC transplantation in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS drives the expansion of Tregs. This increase in Tregs is correlated with an increase in local remyelination. Treg dependent remyelination occurs, even in the absence of cellular reconstitution by transplanted hNSCs. Chapter 3 explores the mechanism by which hNSCs increase the Treg population. Co-cultures of hNSCs with splenocytes revealed that hNSCs drive the conversion of T conventional (Tconv) cells to peripheral Tregs (pTregs) through presentation of self-antigens expressed by hNSCs. Generation of pTregs is not driven by direct interactions with hNSCs as thymically presented self-antigens are sufficient to drive pTreg generation in vitro and in vivo. Chapter 4 further explores the importance of self-antigen recognition and Treg generation by examining a population of cells that at one time expressed the master Treg transcription factor Foxp3, but no longer express Foxp3, known as ‘Ex-Foxp3’ cells. These studies demonstrate that Ex-Foxp3 cells are generated when autoreactive Tconv cells encounter thymically presented self-antigen in the periphery. Furthermore, Ex-Foxp3 cells are present in mice which lack Tregs refuting the paradigm that Ex-Foxp3 cells are the result of loss of function by Tregs. Finally, Ex-Foxp3 cells were demonstrated to contribute significantly to the generation of Tregs when co-cultured with hNSCs suggesting that Ex-Foxp3 cells are poised to generate Tregs when stimulated with self-antigen. The work presented here contributes strongly to our understanding of how the immune system interacts with self-antigens in the periphery as well as the demonstrating the therapeutic potential of Tregs as mediators of remyelination.