# Abnormal T-Cell activation and cytotoxic T-Cell frequency discriminate symptom severity in myalgic encephalomyelitis/chronic fatigue syndrome

## TL;DR

The study finds that different immune system patterns in people with ME/CFS correlate with symptom severity, suggesting distinct underlying disease mechanisms.

## Contribution

The study identifies distinct immune profiles in mild/moderate versus severe ME/CFS patients, linking these to different pathogenesis mechanisms.

## Key findings

- Mild/moderate ME/CFS patients show increased cytotoxic effector molecules and early-immunosenescence cells.
- Severe ME/CFS patients have higher activated lymphocytes and pro-inflammatory cytokines, indicating prolonged inflammation.
- Altered cytotoxic responses are observed across multiple cell types in severe ME/CFS.

## Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating but poorly-understood disease. ME/CFS symptoms include immune system effects alongside incapacitating fatigue and post-exertional disease exacerbation. Symptom severity can range from mild to severe and whilst symptoms can fluctuate, few people fully recover.

Immunological profiles of people living with ME/CFS were analysed by flow cytometry, focusing on cytotoxic cells, to determine whether people with mild/moderate (n = 43) or severe ME/CFS (n = 53) expressed different immunological markers. Flow cytometry data were tested for normality and the two clinical groups were compared by t-test or Mann-Whitney U-test as appropriate.

People with mild/moderate ME/CFS had increased expression of cytotoxic effector molecules alongside enhanced proportions of early-immunosenescence cells, determined by the CD28-CD57- phenotype, indicative of persistent viral infection. In contrast, people with severe ME/CFS had higher proportions of activated circulating lymphocytes, determined by CD69+ and CD38+ expression, and expressed more pro-inflammatory cytokines, including interferon-γ, tumour necrosis factor and interleukin-17, following stimulation in vitro, indicative of prolonged non-specific inflammation. These changes were consistent across different cell types including CD8+ T cells, mucosal associated invariant T cells and Natural Killer cells, indicating generalised altered cytotoxic responses across the innate and adaptive immune system.

These immunological differences likely reflect different disease pathogenesis mechanisms occurring in the two clinical groups, opening up opportunities for the development of prognostic markers and stratified treatments.

The online version contains supplementary material available at 10.1186/s12967-025-07507-x.