Date of Award
Doctor of Philosophy (PhD)
T cells play a central role in the immune response to fight against pathogens and orchestrate other immune cells. An overreactive immune response can lead to autoimmune diseases, therefore the immune system must possess negative regulation mechanisms. In the periphery, naturally arising regulatory T cells (nTregs) negatively regulate immune responses and play an important role in maintaining immune homeostasis. When antigens are present, conventional CD4+ T cells recognize their cognate antigen and proliferate. After pathogen clearance, expanded effector T cells eventually decline in number due to activation induced cell death (AICD) to terminate immune response. However, it is not understood how nTregs respond to antigen stimulation.
We previously discovered the phenomenon that nTregs survive and expand when stimulated with plate-bound anti-CD3/anti-CD28 antibodies, which resemble antigen stimulation in the presence of IL-2, while conventional T cells undergo massive apoptosis. This suggests that there is a differential survival mechanism between nTregs and conventional T cells. Further, we found that T cell death under this stimulation was mediated by a novel form of the apoptotic pathway (p53-induced and CD28-dependent apoptosis; PICA) and distinct from classical AICD.
In my dissertation, I hypothesized that this differential survival mechanism between nTreg and conventional CD4+ T cells against PICA might be important in keeping the balance between nTregs and non-Tregs thus maintaining immune homeostasis in a physiological environment. Therefore, I investigated by which mechanisms nTregs survive under PICA inducing stimuli. I found that at least two signaling pathways are altered in nTregs under PICA induced stimulation thus mediating cell survival.
My work suggests that reduced RasGRP1 expression and TGF-β signaling mediate the survival of nTregs under PICA inducing stimuli. These altered signals in Tregs are likely regulating the balance of nTreg and conventional T cells during an immune response, thus maintaining immune homeostasis.
Takami, Mariko, "Cell Biology of Foxp3+ Regulatory T Cells" (2012). Dissertations. 409.
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Copyright © 2012 Mariko Takami