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Overcoming Self- Reactivity in Type 1 Diabetes via Modulation of Immune Cell Metabolism

Martins, Christina P. (2021) Overcoming Self- Reactivity in Type 1 Diabetes via Modulation of Immune Cell Metabolism. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The immune system is responsible for mediating protection of its host from foreign pathogens, and its ability to do so efficiently is vital to the maintenance of health. Recognition of pathogens relies on a keen ability to discriminate self from non- self in order to minimize detrimental immunopathology against host- tissues. However, under certain circumstances, self- reactive T cells become activated and drive autoimmune targeting of host tissues, like that exhibited in Type 1 Diabetes (T1D). T1D occurs when insulin secreting β cells residing in the pancreas are mistakenly recognized as foreign and targeted for destruction. While various immune cells work cooperatively to mediate β cell death, autoreactive CD4+ T cells are considered the primary contributors to disease pathology. Recent interest in the field of immunometabolism has demonstrated the importance of cellular metabolic programs in the activation and differentiation of immune cells, especially T cells. Specifically upon antigen encounter, T cells become activated and rely on the less efficient aerobic glycolysis to support rapid growth, clonal expansion, and effector functions. Based on the importance of glycolysis in promoting T cell activation and effector function, use of glycolytic inhibitors to suppress autoreactive T cell responses in Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), and Rheumatoid Arthritis (RA) have proven beneficial in alleviating autoimmunity. However, the ability to modulate T cell metabolism in the context of T1D has remained unexplored. Here, we assessed the ability of the small molecule PFK15, a competitive inhibitor of a rate- limiting enzyme in the glycolysis pathway PFKFB3, to suppress autoimmunity during T1D. Our results demonstrated that inhibiting glycolysis reduced diabetogenic T cell responses in vitro, and significantly delayed the onset of T1D in adoptive transfer models. The protective benefits associated with PFK15 treatment were due to induction of terminal CD4+ T cell exhaustion. This phenotype was due to a direct effect on autoreactive T cells, as antigen presenting cell (APC) function was unaltered by PFK15. Collectively, our data support modulating cellular metabolism as a novel approach to controlling aberrant T cell responses in T1D; with broad implications in our understanding of chronic infection, cancer, and autoimmunity.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Martins, Christina P.cpm40@pitt.educpm40
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPiganelli, Jon D.jdp51@pitt.edujdp51
Committee ChairMailliard, Robbie B.rbm19@pitt.edurbm19
Committee MemberMattila, Joshua T.jmattila@pitt.edujmattila
Committee MemberLittle, Steven R.srlittle@pitt.edusrlittle
Date: 27 August 2021
Date Type: Publication
Defense Date: 12 July 2021
Approval Date: 27 August 2021
Submission Date: 12 August 2021
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 195
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Type 1 Diabetes, Immunometabolism, CD4+ T cells, Glycolysis, T cell Exhaustion, PD-1, LAG-3, Autoimmunity
Date Deposited: 27 Aug 2021 17:19
Last Modified: 27 Aug 2021 17:19


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