Thread by @ZdenekVrozina

A new 3-year scRNA-seq study shows something striking. Some people after COVID still carry an immune profile that looks like accelerated aging - low naive T cells and persistent activation of pathogenic Th17. Not a long-COVID cohort, but biologically very close🧵

The study didn’t select people with long COVID.
It followed 47 individuals after COVID-19 for 3 years - and some symptoms were reported within the cohort, allowing the authors to examine symptom-associated immune signals without defining a long-COVID subgroup.

The first major finding.
Even after 3 years, three key protective cell types remain significantly reduced
naive CD4 T cells
naive CD8 T cells
SLC4A10+ MAIT cells
This pattern is normally associated with immunosenescence.

Importantly, the authors corrected for age.
Even after age adjustment, naive T cell levels remained low.
This isn’t getting older.
It’s a lasting imprint of the infection.

Meanwhile, monocytes - heavily involved in acute COVID and early PASC - gradually normalize.
By year 3, they no longer explain the persistent inflammation.
This shifts the focus away from the early innate response.

So what does drive chronic inflammation in years 2 and 3?
The study points to a clear culprit
Pathogenic Th17 cells (LTB+ Th17).
These cells stay elevated and form a long-term inflammatory axis.

LTB+ Th17 cells show a strong pro-inflammatory gene signature and correlate with several cytokines -
IL-17, IL-1β, IL-4, IL-9, IFN-γ.
This is not residual noise - it’s an active, persistent immune program.

Most importantly, the pathogenic Th17 subset shows clear associations with symptoms reported in the cohort - anxiety/depression, chest pain, generalized pain/discomfort, and smell disturbances.
It’s a biological signal behind clinically meaningful complaints.

There’s also a second Th17 subset - RORC+ Th17 - that seems protective.
It shows anti-inflammatory characteristics and is negatively associated with muscle weakness.
The nuance matters - not all Th17 are the same.

What keeps the pathogenic ones activated after 3 years?
Two molecules remain elevated long term
S100A8 (calprotectin)
IL-16
Both act as danger signals.
In vitro, they directly expand LTB+ Th17 cells.

This suggests the virus isn’t needed anymore to maintain the dysregulation.
Persistent alarmin signaling + reduced naive T-cell regeneration = a stable, self-reinforcing immune imbalance.

Sum:
Three years after COVID-19, the cohort shows a pattern where symptom-associated immune signatures involve persistent pathogenic Th17 activation and reduced naive T cells - a biological picture that mirrors long-COVID mechanisms, even without a defined LC cohort.

Three years out, the immune system of many post-COVID individuals still isn’t back to baseline.
Reduced naive T cells + persistent pathogenic Th17 activity form a pattern that would be alarming in any other disease.
COVID-19 leaves a biological footprint we can’t ignore.

Zheng et al., T cell-driven sustained inflammation and immune dysregulation up to three years post-COVID-19, 2025. link.springer.com/article/10.100…

Insides:
This wasn’t a long COVID cohort, yet the study still found clear signs of chronic immune activation.
That means the number of people with quiet post-COVID immune dysregulation may be larger than the number of people formally labeled with long COVID.
LC may be a continuum, not a category.

Immunosenescence isn’t a metaphor here - it’s measurable @TakeWeightOffMD
This isn’t just weaker immunity.
It’s a loss of naive T cells, a hallmark of immune aging.
If this appears in people in their 40s-60s, the immune system becomes effectively older than the body.

If S100A8/A9 - calprotectin - stays elevated for years, it means two things.
Micro damage to tissues may continue even without virus, and
the immune system receives a constant danger signal.

If COVID leaves you with
fewer naive T cells, fewer MAIT cells, a skewed Th17 balance
then each reinfection may hit harder than expected.
The adaptive immune system may not reset fully.

A warning signal
If we saw low naive T cells, chronically elevated IL-17, persistent pathogenic Th17 activation
in any other context, we would call it a chronic inflammatory condition.
The fact that it appears after COVID - yet is often dismissed - is the real red flag. @szupraha @ZdravkoOnline @adamvojtech86

This study doesn’t claim viral persistence - but the biology fits a scenario where something isn’t fully cleared.
Persistent alarmins, pathogenic Th17 activity, and reduced naive T cells create the kind of immune footprint we see when residual proteins or debris keep provoking the system.