Tracking Myelin Specific CD4 T Cells during Demyelinating Disease Post-Infection Público
Cosby, Jennifer Michelle (2017)
Published
Abstract
Multiple sclerosis is a debilitating demyelinating autoimmune disease characterized by the recruitment of myelin-specific CD4 T cells into the CNS. The mechanism for the initiation of this disease, however, has yet to be uncovered. Infections have been proposed as triggers that activate myelin-specific CD4 T cells to begin the process of demyelination. In contrast to this paradigm, our studies reveal that infections are able to provide protection from a well-studied model for demyelinating disease (EAE). In one of our described studies, we generated a molecular mimic (Listeria monocytogenes expressing MOG, or Lm-MOG) to determine if infection can trigger disease symptoms. Lm-MOG did not break tolerance to induce EAE and instead was able to protect from EAE by generating a MOG-specific Treg population that most likely is able to limit the expansion of effector CD4 T cells. However, mice that lack MOG-specific tolerance mechanisms (MOG-/- mice) are not able to generate Tregs to MOG and therefore have a large effector T cell expansion. These effector CD4 T cells are then able to initiate disease symptoms. In addition, the Treg generation observed in wild-type mice was antigen specific as Lm-gp66 did not generate Tregs toward the gp66 antigen. Due to these results, it could be suggested that individuals that lack MOG-specific tolerance mechanism may be at risk for demyelinating disease whereas individuals with MOG-specific tolerance mechanisms intact are able to prevent demyelinating disease through Treg generation. We also infected mice with LCMV during EAE disease course to determine the effects of unaltered infections during EAE. Contrary to the paradigm that infection promotes or exacerbates demyelinating disease, LCMV delayed autoimmune disease in animals. The initiators of EAE, CD4 T cells, were less able to traffic to the CNS compared to uninfected controls. The canonical proinflammatory Th17 response was also impaired in the CNS. High affinity myelin-specific CD4 T cells were also lacking in the CNS compared to uninfected controls. Together, these results explore the role that infections may play in protection against autoimmune disease in individuals with intact tolerance mechanisms.
Table of Contents
Chapter 1: Introduction……………………………………………………………….........1
Figure Legends………………………………….………………………………..……......25
Figure 1 Schematic of molecular mimicry theory...………………………………...………27
Figure 2 Representation of micropipette adhesion frequency assay....…………………...…28
Chapter 2: Antigen specific Tregs are selectively expanded to prevent demyelinating disease...................................................................................................................................................29
Abstract………………………………………………………………………………...…29
Introduction..……………………………………………………………………………...30
Materials and Methods……………………………………………………………………32
Results…………………………………………………………………………………….35
Discussion………………………………………………………………………………...39
Acknowledgements………………………………………………………………………..43
Figure Legends……………………………………………………………………………44
Supplemental Figure Legends……………………………………………………………..48
Figure 1 Infection initiates EAE in genetically susceptible mice.........……………………...50
Figure 2 Myelin specific CD4 T cell expansion is limited post-infection....………………...51
Figure 3 LLO specific CD4 T cells are correlated in MOG-/-, but not C57Bl/6, mice..…...52
Figure 4 Tregs expanded in wild-type mice but not genetically susceptible mice.........……...53
Supplemental Figure 1…………………………………………………………….………54
Supplemental Figure 2…………………………………………………………….………55
Chapter 3: LCMV Delays EAE by limiting high affinity myelin CD4 T Cell Responses......56
Abstract………………………………………………………………………………...…56
Introduction..……………………………………………………………………………...57
Materials and Methods……………………………………………………………………59
Results…………………………………………………………………………………….62
Discussion………………………………………………………………………………...66
Acknowledgements………………………………………………………………………..70
Figure Legends……………………………………………………………………………71
Supplemental Figure Legends……………………………………………………………..76
Figure 1 EAE is less severe and delayed during LCMV infection…..……………………...77
Figure 2 LCMV reduced the CD4 T cell response……………….………………………...78
Figure 3 Cytokine profile is altered post-infection…………………….…………………...79
Figure 4 Myelin specific CD4 T cells are reduced in the CNS post-infection….…………...80
Figure5 High affinity MOG-specific CD4 T cells are absent post-infection..........…………81
Supplemental Figure 1…………………………………………………………….………82
Chapter 4: Discussion.........……………………………………………………….………83
Figure Legends……………………………………………………………………………88
Figure 1 Model for molecular mimicry induced demyelinating disease..........................……...89
Literature Cited ………………………………………………………………………….90
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