Single-cell analysis reveals immune remodeling of monocytes, NK cells, T cell exhaustion, and Galectin-9-associated depletion of gamma delta and mucosal-associated invariant T cells in Long COVID with ME/CFS. — CFSMEATLAS
Single-cell analysis reveals immune remodeling of monocytes, NK cells, T cell exhaustion, and Galectin-9-associated depletion of gamma delta and mucosal-associated invariant T cells in Long COVID with ME/CFS.
Shahbaz, Shima, Bozorgmehr, Najmeh, Rahmati, Amirhossein et al. · Frontiers in immunology · 2026 · DOI
Quick Summary
Researchers analyzed immune cells from Long COVID patients with ME/CFS symptoms one year after COVID-19 infection and compared them to people who recovered normally. They found that Long COVID patients have significant problems with multiple immune cell types: fewer protective T cells, exhausted immune cells, and excessive inflammation markers. Interestingly, Long COVID patients showed different immune changes compared to people with ME/CFS from other causes, suggesting Long COVID may damage the immune system in a distinct way.
Why It Matters
This study provides the first detailed cellular mechanism distinguishing Long COVID-associated ME/CFS from idiopathic ME/CFS, revealing that post-COVID ME/CFS involves distinct immune dysregulation patterns. Identifying the Galectin-9-TIM-3 pathway as a potential driver of immune cell depletion offers a concrete therapeutic target that could be tested in future interventions. These findings establish measurable immune biomarkers that could improve diagnosis, patient stratification, and development of targeted treatments for Long COVID.
Observed Findings
Long COVID-ME/CFS patients showed marked reductions in naïve CD4+ and CD8+ T cells, regulatory T cells, MAIT cells, and gamma-delta T cells compared to recovered controls.
Natural killer (NK) cells in Long COVID patients displayed reduced frequency and altered activation markers suggesting impaired cytotoxic function.
Monocytes in Long COVID patients demonstrated reduced expression of phagocytosis-related genes and increased pro-inflammatory cytokine gene expression.
Idiopathic ME/CFS patients exhibited less severe immune alterations, with preserved MAIT and NK cell populations and evidence of T cell activation without exhaustion.
Galectin-9-TIM-3 pathway interaction was identified as a potential mechanism driving depletion of gamma-delta and MAIT cells in Long COVID.
Inferred Conclusions
Long COVID-associated ME/CFS involves distinct and more extensive peripheral immune remodeling compared to idiopathic ME/CFS, suggesting different underlying pathophysiology.
Chronic immune activation and dysregulation in Long COVID may be driven in part by the Galectin-9-TIM-3 signaling pathway.
The immune cell abnormalities observed (reduced protective T cells, NK cell dysfunction, and monocyte skewing toward inflammation) could serve as cellular biomarkers for Long COVID-ME/CFS diagnosis and prognosis.
Remaining Questions
Do these immune alterations persist beyond 12 months post-infection, or do they resolve over longer timeframes?
What This Study Does Not Prove
This study does not prove that the identified immune changes are the primary cause of ME/CFS symptoms—they may be consequences of infection rather than disease drivers. The findings are correlative and limited to one timepoint (12 months post-infection); longitudinal data would be needed to establish whether these changes precede, coincide with, or follow symptom onset. The single-cell transcriptional signatures do not directly demonstrate functional impairment of these cells, which would require additional functional assays.
What is the functional significance of these transcriptional changes—do they actually impair immune cell ability to fight infections or control inflammation?
Can Galectin-9-TIM-3 pathway blockade reverse the depletion of gamma-delta and MAIT cells, and would this improve clinical symptoms?
What triggers the shift toward pro-inflammatory monocyte activation in Long COVID, and can this be targeted therapeutically?