The Role of T-Cell Exhaustion as a Driver in the Development of Post-Acute Infection Syndromes: A Literature Review

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.