Mechanistic insights into how collective effects mediate the T cell response
Name
yin-roseyin-phd-cheme-2025-thesis.pdf
Description
Thesis PDF
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2.09 MB
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Adobe PDF
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86b16d1476595b2cc82c49c2909e4e93
Author(s)
Yin, Rose
Advisor(s)
Chakraborty, Arup K.
Date Issued
May 2025
Publisher
Massachusetts Institute of Technology
Abstract
T cells play an important role in the adaptive immune system by providing robust responses to foreign pathogens while avoiding widespread autoimmunity. Although many specific microscopic factors are thought to contribute to this self/non-self discrimination, based on a theoretical paper and experiments, a generalized mechanistic framework has emerged over the past decade to describe the remarkable robustness of self/non-self discrimination in spite of the presence of autoimmune T cells in every host. This quorum threshold mechanism states that a threshold number of T cells (a quorum) must be activated by a foreign antigen in a local area for an immune response to ensue. In my thesis, I use analytical and computational models to show how this mechanism enables a response against foreign pathogens while tolerating exposure to self-tissue, and how it increases robustness against perturbations such as changed self-antigen presentation or increased epitope spreading due to inflammation. However, under persistent or severe infections, these models also show that the risk of autoimmunity increases through enhanced sampling of rare epitopes and activation of cross-reactive T cells. These results provide a potential explanation for why persistent infections often trigger autoimmune diseases. To further understand the emergence of the quorum threshold, I developed a population dynamics model. Our results show that steady states corresponding to an effective or ineffective immune response are separated by a threshold dependent on both activated T cell population concentration and concentration of a growth factor (IL2) that is secreted by T cells and absorbed by cells that dampen the immune response. Notably, the threshold’s existence proves robust across randomized parameters, highlighting its fundamental role in regulating T cell responses.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
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