Date of Award
Doctor of Philosophy (PhD)
How autoimmune diseases are regulated is a long-term research topic in the autoimmunity field. We use autoimmune diabetes as a model to study this. Autoimmune diabetes is a T cell-dependent autoimmune syndrome. The functions of T cells are regulated during their development and activation. Developmentally, T cells will undergo a stringent thymic selection: a process that self-reactive T cells are tolerized to become thymic derived Tregs or can be deleted by apoptosis based on binding affinity and avidity between the TCRs and self-peptide:MHC complexes. After T cells mature, they can also be tolerized in the periphery in many other ways, such as periphery induced regulatory T cell (pTreg) development, T cell energy, and T cell exhaustion. pTregs generated extrathymically contribute to immune regulation of a given anatomical site. T cells anergy makes the T cells intrinsically functionally inactivated upon an antigen encounter, a process occurring during T cell priming due to the absence of costimulatory signals. T cells would remain alive but stay in a hyporesponsive state. Exhausted T cells can be functionally activated and differentiated into effector cells, but due to the constant antigen exposure and TCR activation, these T cells gradually lose the expression of the effector molecules at the same time express a series of inhibitory molecules that maintain a hypofunctional status. In this thesis we mainly examined the functional changes of the exhausted CD8 T cells in islets after immune checkpoint blockade, a condition where facilitated diabetes progression occurs. This allows us to understand how T cell exhaustion and subsequent immunoregulation are established in autoimmune diabetes.Briefly, we found blockade of PD-1/PD-L1 axis but not CTLA-4 promoted diabetes progression in non-obese diabetic (NOD) mice. Both CD4 and CD8 T cells responded to PD-1 blockade to proliferate. This was highly dependent on T cells as antibody depletion of CD4 or CD8 T cells rescued anti-PD-1 diabetogenic effect. Moreover, we noticed that PD-1/PD-L1 regulation was functionally established in islets as islet T cells were sufficient to induce diabetes upon PD-1 blockade. Exhausted CD8 T cells expanded during diabetes progression. We identified two subsets of exhausted CD8 T cells in islets: precursor exhausted T cells and terminally differentiated exhausted T cells. In inflamed islets without anti-PD-1 treatment, most of the CD8 T cells were exhausted T cells and more than 70% of the exhausted CD8 T cells were precursor exhausted T cells; however, after PD-1 blockade, these precursor exhausted T cells differentiated into terminally differentiated exhausted T cells that expressing a large wave of effector molecules which contributed to the acute diabetes progression. In addition to T cells, we found that macrophage was another set of cells that underwent dramatic changes following PD-1 blockade. After anti-PD-1 treatment, macrophages became highly activated, acquiring elevated signatures of NF-κB signaling and IFNγ signaling which derived from their interaction with β cells and T cells, respectively. One subset of macrophages was derived from monocyte and these monocyte-derived macrophages displayed higher pro-inflammatory activity and can be recruited by activated T cells. The activated macrophages were cytocidal to β cells through nitric oxide (NO) production. Depleting monocytes with clodronate or inhibiting NO with aminoguanidine significantly reduced the incidence of PD-1 blockade induced diabetes. Therefore, we identified a novel killing component causing acute diabetes in context of PD-1 blockade. Our findings may help design treatment regimes in cancer immunotherapy to avoid autoimmune side effects.
Chair and Committee
Emil R. Unanue
Wayne M. Yokoyama, Paul M. Allen, Marco Colonna, Ali H. Ellebedy,
Hu, Hao, "The immunoregulation of autoimmune diabetes" (2021). Arts & Sciences Electronic Theses and Dissertations. 2501.