Thread by @ZdenekVrozina

A new study in European Journal of Immunology (Mouton et al., 2025) followed hundreds of patients after COVID-19.
Their goal: understand why some people develop persistent symptoms - Long COVID / PASC.
The answer? T cells that never stand down.🧵

They followed over 450 people - both mild and severe COVID.
Findings:
40% of mild cases had PASC (sic)
57% of severe cases had PASC
But the key difference wasn’t viral load or inflammation.
It was how the immune system looked months later!

Blood tests showed:
No viral RNA
No spike protein in plasma
No strong systemic inflammation
But T cells told a different story:
The immune system was still on high alert.

Patients with PASC had elevated TEMRA T cells (CD45RA+ effector memory cells).
These are terminally differentiated CD4+ and CD8+ T cells - cells that have “seen war” and didn’t return to baseline.
Long-lived. Hyperactive. And often dysregulated.

These T cells showed:
CD57+ - chronic stimulation, low proliferative capacity
T-bet+ - effector programming
CXCR3↓ and CD27↓ - altered migration and costimulation
A profile consistent with persistent immune reprogramming.

Interestingly, the strongest T cell responses weren’t to spike.
They were directed against nucleocapsid (N) and membrane (M) proteins - antigens not present in vaccines.
This suggests a unique imprinting from natural infection!

And crucially:
These T cells secreted cytokines even without stimulation - including IFN-γ and TNF-α.
This is like having an immune system that keeps pulling the fire alarm - even when the fire is out.
A recipe for chronic dysfunction.

So what we see is:
No virus in blood
But long-lived, overstimulated T cells
With a phenotype seen in other chronic infections - but here, triggered by a single SARS-CoV-2 exposure.

Enter: CD57

CD57 isn’t just a surface marker.
It’s a molecular scar - a sign that the T cell has undergone repeated stimulation and reached a terminal state.
Low replication. Persistent activity.
Sometimes called "immune senescence."

A second study (Bendíčková et al., 2025) focused specifically on CD57+ CD8+ T cells after COVID.
They found:
These cells persist for many months
Have low Ki-67 (proliferation)
But retain cytotoxic potential
And correlate with long COVID symptoms in some researchgate.net/publication/39…

Third piece:
Lucena Lage et al. (2025)
They identified SARS-CoV-2–specific CD8+ TEMRA cells with:
CD57+, TIGIT+
Granzyme B+, Perforin+ (cytotoxic)
Low proliferation
Persistence up to 12 months
These aren’t benign memory cells. medrxiv.org/content/10.110…

Putting it together:
PASC isn’t explained by blood virus
But it is associated with persistent T cell activation
CD57+ TEMRA cells stick around for months to a year
And they produce inflammatory and cytotoxic signals - without supervision

These aren’t just markers - they may be part of the mechanism.
Persistent TEMRA T cells = poor responders to new infections
Poor regulation
Cytotoxicity without clear targets
Chronic tissue irritation, especially in sensitive systems (eg nervous, vascular)

This is not unique to COVID.
We see similar cells in:
HIV: exhausted CD8+ T cells (often CD57+, TIGIT+)
CMV: CD57+ TEMRA expansion, especially in older adults
Cancer: T cell dysfunction under chronic stimulation
But COVID seems to create this after one acute infection.

Even a short infection can push the immune system into a state that resembles chronic immune aging
and this can last months to years

How long does it last?
Mouton: 6–9 months
Lage: up to 12 months
Bendíčková: CD57+ CD8+ cells found many months post-COVID, even in younger people
This is not a short-term post-viral state

CD57⁺ TEMRA cells are known to:
Have impaired response to new pathogens
Resist apoptosis
Produce low-level inflammation
Persist for years in CMV and HIV patients
There’s no reason for now to think COVID is fundamentally different

This may help explain:
fatigue
neuroinflammation
poor vaccine responses post-COVID
increased risks of reinfection, autoimmunity, or other organ dysfunctions in some
It’s not just "recovery taking longer."
It's immune remodeling.

CD57+ TEMRA cells are not the full answer - but they are a consistent thread across studies.
They offer us a window into post-COVID immune dysfunction.
And maybe, one day, a way out.

Mouton et al. (2025) – Alpha & Delta (2020–2022)
Bendíčková et al. (2025) – mainly Delta and early Omicron (BA.1)
Lucena Lage et al. (2025) – exclusively Omicron (BA.1/BA.2)
CD57+ TEMRA cells show up across all variants.
It's a pan-pandemic signature.

Mouton et al., 2025, European Journal of Immunology. Immunological and Clinical Markers of Post-acute Sequelae of COVID-19: Insights from Mild and Severe Cases 6 Months Post-infection. onlinelibrary.wiley.com/doi/10.1002/ej…