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

Autor:	Martins CP; Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Pediatric Surgery, Rangos Research Center, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States., New LA; Department of Pediatric Surgery, Rangos Research Center, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States., O'Connor EC; Department of Pediatric Surgery, Rangos Research Center, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States., Previte DM; Department of Pediatric Surgery, Rangos Research Center, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States., Cargill KR; Department of Pediatrics, Rangos Research Center, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States., Tse IL; Department of Pediatric Surgery, Rangos Research Center, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States., Sims-Lucas S; Department of Pediatrics, Rangos Research Center, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States., Piganelli JD; Department of Pediatric Surgery, Rangos Research Center, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Jun 07; Vol. 12, pp. 669456. Date of Electronic Publication: 2021 Jun 07 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.669456
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Martins, New, O’Connor, Previte, Cargill, Tse, Sims- Lucas and Piganelli.)
Databáze:	MEDLINE
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