Abstract
T lymphocytes constitute a major effector cell population in autoimmune type 1 diabetes. Despite essential functions of mitochondria in regulating activation, proliferation, and apoptosis of T cells, little is known regarding T cell metabolism in the progression of human type 1 diabetes. In this study, we report, using two independent cohorts, that T cells from patients with type 1 diabetes exhibited mitochondrial inner-membrane hyperpolarization (MHP). Increased MHP was a general phenotype observed in T cell subsets irrespective of prior antigen exposure, and was not correlated with HbA1C levels, subject age, or duration of diabetes. Elevated T cell MHP was not detected in subjects with type 2 diabetes. T cell MHP was associated with increased activation-induced IFNγ production, and activation-induced IFNγ was linked to mitochondria-specific ROS production. T cells from subjects with type 1 diabetes also exhibited lower intracellular ATP levels. In conclusion, intrinsic mitochondrial dysfunction observed in type 1 diabetes alters mitochondrial ATP and IFNγ production; the latter is correlated with ROS generation. These changes impact T cell bioenergetics and function.
Highlights
Increasing evidence suggests that type 1 diabetes patients exhibit immune dysregulation, most notably, a propensity towards pro-inflammatory innate immune activities and aberrant adaptive T cell responses[1]
When T cells interact with antigen presenting cells (APCs) through HLA/ antigen-T cell receptor (TCR) engagement, mitochondria within T cells are translocated to the region of the cytoplasm directly adjacent to the immunological synapse
Mitochondrial metabolic activity plays a central role in regulating T cell activation, proliferation, and programmed cell death[4]
Summary
Increasing evidence suggests that type 1 diabetes patients exhibit immune dysregulation, most notably, a propensity towards pro-inflammatory innate immune activities and aberrant adaptive T cell responses[1]. Despite this apparent deficit in immune tolerance, the cellular and molecular contributors to this process remain poorly characterized. Through a balanced process of fission and fusion, mitochondria maintain inner-membrane potential (ΔΨm), generate ATP, control local calcium concentrations, and produce mitochondrial ROS (mtROS)[5, 6] This generation of mtROS is essential for IL-2 production and proliferation[7]. Functional studies provided evidence that T cell MHP was linked with altered mitochondrial and cytokine responses from T cells of patients with type 1 diabetes after TCR stimulation
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
