T Cell Ca2+ Signal Dynamics: An Emerging Landscape for Therapeutic Strategies

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: 30 September 2025 | Viewed by 518

Special Issue Editors


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Guest Editor
Department of Pharmaceutical Sciences, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA
Interests: calcium signaling; SERCA regulation; T cell signaling; ER calcium stores; Ca2+ release

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Guest Editor
Institute for Neuroimmunology and Multiple Sclerosis Research, Göttingen, Germany
Interests: blood-brain barrier; immune cells; multiple sclerosis; experimental autoimmune encephalomyelitis; two-photon microscopy; B cells; T cells; Dendritic cells; macrophages; astrocytes; microglia; oligodendrocytes; neurons; central nervous system; autoimmune disease; ion channels; calcium signaling
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Special Issue Information

Dear Colleagues,

T lymphocytes have evolved a considerable reliance on the induction and management of the intracellar Ca2+ signal. The foundation of the adaptive immune response is critically dependent on the T cell’s recognition of an antigen and the immediate transduction of antigen recognition via the T cell receptor’s recruitment of a multiplex Ca2+ signal. T cell-activated Ca2+ signals then proceed according to a complex trajectory, with an initial increase in cytoplasmic Ca2+ due to inositol 1,4,5-trisphosphate-mediated release from internal Ca2+ stores, followed by a Ca2+ influx phase due to the activation of plasma membrane-localized Orai Ca2+ channels gated by ER Ca2+ store depletion signals. Importantly, in the absence of the successful deployment of the Ca2+ influx signal, which can occur over protracted periods of T cell engagement with antigen-presenting cells, T cells fail to be adequately activated, resulting in impaired immune function. Thus, there are several key points where the regulation of the T cell Ca2+ signal is important, from the management of ER Ca2+ store status to pathways linked to PM Ca2+ channel activation, all of which warrant closer examination. This could allow us to achieve greater clarity regarding their complex roles and to identify novel targets for therapeutic intervention in cases of immune dysfunction. These topics represent key domains in T cell signaling investigations. This Special Issue will provide a platform for sharing important contributions to this rapidly advancing field in T cell signaling science.

Dr. David W. Thomas
Dr. Marc André Lécuyer
Guest Editors

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Keywords

  • T cell signaling
  • Ca signaling
  • TCR-activated signals
  • ER Ca release
  • ER Ca stores
  • store-operated Ca influx
  • ER Ca store depletion signals

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Published Papers (1 paper)

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Research

26 pages, 3018 KiB  
Article
High Glucose in Diabetic Hyperglycemia Perturbs Lymphocyte SERCA-Regulated Ca2+ Stores with Accompanying ER Stress and Signaling Dysfunction
by Md Nasim Uddin, James L. Graham, Peter J. Havel, Roshanak Rahimian and David W. Thomas
Biomolecules 2025, 15(7), 987; https://doi.org/10.3390/biom15070987 - 11 Jul 2025
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Abstract
It is well recognized that patients with type 2 diabetes mellitus (T2DM) exhibit significant impairment of immune function resulting in a higher frequency of infections. We hypothesize in this study that a likely contributor to immune dysfunction in T2DM is alteration of T [...] Read more.
It is well recognized that patients with type 2 diabetes mellitus (T2DM) exhibit significant impairment of immune function resulting in a higher frequency of infections. We hypothesize in this study that a likely contributor to immune dysfunction in T2DM is alteration of T lymphocyte signaling functions induced by chronic hyperglycemia. In this study we have utilized the established UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rat model of human T2DM to investigate whether progressive hyperglycemia diminishes T cell receptor (TCR)-releasable endoplasmic reticulum (ER) Ca2+ stores, an essential early antigen-stimulated signal driving T cell activation. Furthermore, results from this study demonstrate that chronic hyperglycemia markedly alters the expression profile of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) Ca2+ ion pumps, which are the major enzymatic ion transporters maintaining replenished TCR-sensitive Ca2+ pools. We conducted companion experiments using Jurkat T lymphocytes exposed to high glucose which allowed finer resolution of early disruptions to ER Ca2+ store integrity and greater clarity on SERCA isoform-specific roles in diabetes-induced Ca2+ signal dysregulation. In summary, these experiments suggest that hyperglycemia in T2DM drives an ER stress state manifesting in reduced expression of the SERCA pumps, erosion of ER Ca2+ stores and culminating in T cell and immune dysfunction. Full article
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