Glycolysis Inhibition Induces Functional and Metabolic Exhaustion of CD4+ T Cells in Type 1 Diabetes

Abstract

In Type 1 Diabetes (T1D), CD4+ T cells initiate autoimmune attack of pancreatic islet β cells. Importantly, bioenergetic programs dictate T cell function, with specific pathways required for progression through the T cell lifecycle. During activation, CD4+ T cells undergo metabolic reprogramming to the less efficient aerobic glycolysis, similarly to highly proliferative cancer cells. In an effort to limit tumor growth in cancer, use of glycolytic inhibitors have been successfully employed in preclinical and clinical studies. This strategy has also been utilized to suppress T cell responses in autoimmune diseases like Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA). However, modulating T cell metabolism in the context of T1D has remained an understudied therapeutic opportunity. In this study, we utilized the small molecule PFK15, a competitive inhibitor of the rate limiting glycolysis enzyme 6-phosphofructo-2-kinase/fructose-2,6- biphosphatase 3 (PFKFB3). Our results confirmed PFK15 inhibited glycolysis utilization by diabetogenic CD4+ T cells and reduced T cell responses to β cell antigen in vitro. In an adoptive transfer model of T1D, PFK15 treatment delayed diabetes onset, with 57% of animals remaining euglycemic at the end of the study period. Protection was due to induction of a hyporesponsive T cell phenotype, characterized by increased and sustained expression of the checkpoint molecules PD-1 and LAG-3 and downstream functional and metabolic exhaustion. Glycolysis inhibition terminally exhausted diabetogenic CD4+ T cells, which was irreversible through restimulation or checkpoint blockade in vitro and in vivo. In sum, our results demonstrate a novel therapeutic strategy to control aberrant T cell responses by exploiting the metabolic reprogramming of these cells during T1D. Moreover, the data presented here highlight a key role for nutrient availability in fueling T cell function and has implications in our understanding of T cell biology in chronic infection, cancer, and autoimmunity.

Enhanced T Cell Glucose Uptake Is Associated With Progression of Beta-Cell Function in Type 1 Diabetes

“…Enhanced T cell metabolism was also detected in NOD mice and when prediabetic NOD mice were treated with 2-deoxyglucose to block aerobic glycolysis, islet antigen-specific T cell frequency and islet infiltrating lymphocytes decreased, beta-cell degranulation was improved ( 21 ). Similarly, in the adoptive transfer model of T1D, a competitive inhibitor of the glycolytic rate-limiting enzyme of CD4 + T cells reduced T cell responses to β cell antigen in vitro , thus reducing the immunopathological parameters associated with disease onset as 57% of animals remaining euglycemic at the end of the study period ( 22 ). Other studies also found that there are some potential immunotherapy drugs for T1D by inhibiting the T cell glucose metabolism pathway ( 51 – 53 ).…”

Downregulation of TCF1 in HIV Infection Impairs T-cell Proliferative Capacity by Disrupting Mitochondrial Function

“…The change in metabolic features of T-cells during chronic infections has been explored in recent years ( Bengsch et al, 2016 ). The consensus among researchers is that metabolism can affect T-cell development ( Sun et al, 2021 ), proliferation ( Sabharwal et al, 2018 ; Fultang et al, 2020 ), effector function ( Barili et al, 2021 ), and exhaustion ( Martins et al, 2021 ). Moreover, as the energy centers of cell activities, mitochondria are also critical for maintaining T-cell function ( Vardhana et al, 2020 ; Yu et al, 2020 ).…”

New Developments in T Cell Immunometabolism and Therapeutic Implications for Type 1 Diabetes

“…In contrast, activation of mTOR signaling facilitates glycolysis, fatty acid production, and mitochondrial biogenesis (42,45,46). As mentioned above, autoreactive CD4+/CD8+ T cells exhibit a higher level of glycolysis and depend less on OXPHOS, thus suggesting that glycolysis could be used as an attractive therapeutic target (47). Inhibiting mTOR signaling with rapamycin or enhancing the AMPK signaling pathway with metformin are known to reduce glycolysis (19).…”

“…PFK15, a competitive inhibitor of the rate-limiting glycolysis enzyme, has been found to suppress glycolysis utilization of CD4+ T cells and decrease the response of CD4+ T cells to b-cell antigens. Additionally, treatment of PFK15 in NOD mouse models delayed T1D onset due to metabolic and functional exhaustion of T cells (47). In addition, peroxisome proliferator-activated receptors (PPARs) are transcription factors that control genes involved in glucose and lipid metabolism and FAO (90)(91)(92).…”