Type 1 Diabetes (T1D) is an autoimmune disease characterized by islet -specific T cells that infiltrate the pancreas and destroy the β-cells, crippling the necessary supply of insulin to control blood glucose levels. Although the disease can be managed by blood glucose monitoring, insulin injections and strict dietary regimens, there is currently no cure and complications continue to cause significant morbidity and mortality.
Immunotherapies designed to inhibit islet-specific T cells are an attractive approach to treat T1D. Antibodies blocking the Interleukin-7/Interleukin-7 Receptor α (IL-7/IL-7Rα) pathway, which is critical for naïve and memory T cell survival, have shown promise in the non-obese diabetic (NOD) mouse model. Systemic administration of anti-IL-7Rα antibodies have prevented and reversed T1D in these models. However, hyperglycemia returned upon cessation of treatment, indicating no durable tolerance was established. Because of these results, I sought to better understand the mechanisms underlying the impact of IL-7Rα blockade on conventional islet-specific T cells and regulatory T cells (Tregs). I hypothesized that IL-7 signaling blockade (1) altered metabolism leading to impaired diabetogenic T cell effector functions and (2) impaired Tregs in peripheral tissues, potentially diminishing the therapeutic activity of anti-IL-7Rα antibodies.
The data show that IL-7 signaling blockade impaired mitochondrial respiration independent of calcium signaling and downstream proteins. Impaired respiration shifted T cells to a more inefficient metabolic state. These inefficiencies were associated with diminished pro-inflammatory cytokine production. The cell-intrinsic role of IL-7 signaling in Tregs was assessed by crossing floxed IL-7Rα NOD mice with NOD mice that expressed Cre recombinase exclusively in Foxp3+ Tregs. At the onset of T1D IL-7Rα-deficient Tregs presented in lower frequencies than IL-7Rα-sufficient Tregs in pancreatic lymph nodes, and expressed higher levels of the co-inhibitory receptors PD-1 and TIGIT, indicating a more exhausted phenotype. Importantly, NOD mice with IL-7Rα-deficient Tregs developed T1D earlier.
The data presented herein show that IL-7 signaling regulates T cell mitochondrial metabolism, T cell effector function, and identifies a role for IL-7 in the survival and function of Tregs in peripheral tissues during T1D development. This work simultaneously validates the IL-7 pathway as a potential immunotherapeutic target to modulate islet-specific T cells and cautions that unintended effects on protective Tregs must be taken into account for therapeutic strategies.
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/44020 |
| Date | 14 March 2022 |
| Creators | Jones IV, Albert Richard |
| Contributors | Dooms, Hans |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
| Rights | Attribution-NoDerivatives 4.0 International, http://creativecommons.org/licenses/by-nd/4.0/ |
Page generated in 0.0133 seconds