Qeios have published an article entitled ‘The Role of T-Cell Exhaustion as a Driver in the Development of Post-Acute Infection Syndromes' (Gielen et al 2025) which is a review summary of recent studies on T cell exhaustion. It examines its role in post-acute infection syndromes (PAIS), including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long Covid.
Abstract
This literature review summarizes recent studies on T cell exhaustion and its role in post-acute infection syndromes (PAIS), including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long COVID. It synthesizes the current evidence on how persistent immune dysfunction contributes to the chronic symptoms seen in these conditions. T cell exhaustion, marked by continuous antigen exposure, diminished effector function, and increased expression of inhibitory receptors such as PD-1, CTLA-4, TIM-3, and TIGIT, is increasingly recognized as a key factor in the pathogenesis of PAIS. Clinical and molecular studies have revealed altered T cell populations, impaired proliferative responses, and metabolic dysregulation in affected patients.
Persistent viral antigens are implicated in maintaining this exhausted state, whereas neuroimmune interactions and autoimmune processes may further sustain symptomatology. Although this review did not employ a formal systematic methodology, it integrated findings from multiple studies to provide a comprehensive overview of the field. Challenges remain regarding standardized diagnostic criteria and biomarkers; however, advances in immune exhaustion markers present the potential for improved diagnosis and targeted treatments. Emerging therapeutic approaches include immune checkpoint modulation, metabolic interventions, antiviral therapy, and immunomodulation. Further research is needed to clarify the mechanisms, validate the biomarkers, and develop effective clinical interventions. Recognizing T cell exhaustion as a central mechanism offers a foundation for advancing our understanding and management of PAIS.
MEA Comment
T cell exhaustion is an aspect of immune system dysfunction that is being explored at the ME Biobank – which is funded by the MEA Ramsay Research Fund
This new paper contains a literature review of this important aspect of immune system dysfunction in ME/CFS
- Cellular Immune Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) | Cliff et al 2019
- Research: Immune T cells become exhausted in ME/CFS Cornell University, New York | December, 2024
Information on T Cells
All you need to know about T cells:
T cells are a type of white blood cell that play a crucial role in the immune system's defense against infections and diseases.
They originate in the bone marrow and mature in the thymus, hence their name “T” cells. These cells are essential for both cell-mediated and, to some extent, humoral immunity.
SUBTYPES:
- Helper T cells (CD4+) help to activate other immune cells, including B cells (which produce antibodies) and cytotoxic T cells, to fight infections.
- Cytotoxic T cells (CD8+) are also known as killer T cells. These cells directly destroy infected or cancerous cells.
- Regulatory T cells (Tregs) help control and suppress immune responses, preventing autoimmune reactions and maintaining immune homeostasis.
- Memory T cells remain in the body after an infection is cleared, providing long-term immunity and a faster response upon re-exposure to the same pathogen.
WHAT DO T CELLS DO?
- Defense against pathogens: T cells are crucial for protecting the body against viruses, bacteria, fungi, and other pathogens.
- Immune surveillance: They play a role in identifying and eliminating cancerous cells.
- Autoimmunity: Defects in T cell function can lead to autoimmune diseases where the immune system attacks the body's own tissues.
- Allergies: T cells are also involved in allergic reactions.
Dr Charles Shepherd,
Trustee and Hon. Medical Adviser to the ME Association,
Member of the 2018-2021 NICE guideline on ME/CFS committee,
Member of the 2002 Chief Medical Officer's Working Group on ME/CFS
Further Information
- The ME Association: Blood abnormalities found in people with Long Covid | August, 2022