Investigating the Germinal Center Localization of T Follicular Regulatory Cells in PTEN- ΔTReg Mice
Delfin, Edwin O.
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CitationDelfin, Edwin O. 2019. Investigating the Germinal Center Localization of T Follicular Regulatory Cells in PTEN- ΔTReg Mice. Master's thesis, Harvard Medical School.
AbstractGerminal center (GC) formation is essential for orchestrating antigen specific B cellmediated immune responses. During the GC reaction, T follicular helper (Tfh) cells provide the limiting source of survival signals to GC B cells which ensures that only B cells of the highest affinity survive to differentiate into plasma cells and memory B cells. Recently, a subpopulation of effector regulatory T cells (TReg) known as T follicular regulatory (Tfr) cells have been identified that home to the B cell follicle and regulate GC size and activity. Although their precise mechanism remains unclear, it has been shown that Tfr cells promote the production of high affinity antigenspecific antibodies. Published and unpublished work suggest that control of phosphoinositide 3-kinase (PI3K) by the phosphatase PTEN is crucial for Tfr suppressive function, as mice lacking PTEN specifically in the TReg compartment have larger GCs and impaired production of high affinity antigen-specific antibodies. The PI3K signaling pathway is known to be important for cell migration, and we wondered if impaired suppressive capacity is due to mis-localization of PTENdeficient Tfr cells. It is suggested that Tfr cells can make direct contact with GC B cells or Tfh cells, therefore mis-localized PTEN-deficient Tfr cells that are unable to physically interact with their targets may explain their suppressive defect. Using immunofluorescence with multispectral imaging techniques, we quantified Tfr cell localization in the GC and B cell follicle in both control and PTEN-ΔTReg mice. We have observed a decrease in the Tfr to Tfh cell ratio within the germinal centers of PTEN-ΔTReg mice compared to Foxp3 Cre mice. However, these data also suggest that Tfr cells lacking PTEN have no absolute defect in localizing to the GC, so reasons other than a defect in localization likely contribute to the dysfunction of Tfr cells in PTEN-ΔTReg mice.
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