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Immunization With Recombinant Myelin Oligodendrocyte Glycoprotein Identifies Autoreactive T Cells As A Limiting Factor In Autoreactive Germinal Center Maintenance

Jain, RW;

Germinal center (GC) responses are responsible for the protection provided by
immunizations but can also drive autoimmunity. B and T cells collaborate in the GC to
target the same antigen (Ag) to inform B cell differentiation; however, the properties of
Ags differ substantially in autoimmunity and foreign-Ag driven immunity. Currently, it is
not well understood how properties of the Ag itself influence the initiation or progression
of GC responses, limiting our ability to develop effective vaccinations and predict the
progression of autoimmune responses. The purpose of this thesis is to assess how GC
responses initiate and progress when immunizing with an autoAg relative to a model
foreign-Ag. It was hypothesized that autoreactive GCs would be relatively short-lived and
less productive than foreign-Ag driven GCs due to limiting properties of the autoAg. To
address this hypothesis, we developed a modular protein expression system to purify
large amounts of myelin oligodendrocyte glycoprotein (MOG), a commonly targeted
autoAg in Multiple Sclerosis (MS), and streamlined the modification of the MOG
protein’s properties. Relative to immunization with a model foreign-Ag, immunization
with MOG induces a short-lived GC that collapses early forming a large numbers of
memory B cells. Memory B cells generated from the MOG-induced GC are capable of
participating in secondary GCs, however, these memory cells are short-lived resulting in
a short window in which MOG-specific memory B cells can be engaged. The progression
of the MOG-induced GC is then shown to be limited by low T cell Ag-affinity. A
possible explanation for how Ag-properties affect GC progression, is that Ag-properties
influence how B and T cells communicate with each other. To address this hypothesis,
reporters capable of monitoring the activation status of B and T cells were generated
although, attempts to generate mice carrying these reporters were unsuccessful. Overall,
these results confirm that properties of Ags affect the progression of GC responses and
that the MOG-induced GC is limited by properties of the MOG autoAg. These results
have important implications for future vaccine design but also gives insight into how
autoreactive B cells may expand in MS.