COVID can cause a long-lasting breakdown of immune homeostasis, where elevated IL-7 and IL-15 keep T cells activated for months after the acute infection.
In some people this dysregulated state becomes persistent - and may directly contribute to long COVID🧵
In some people this dysregulated state becomes persistent - and may directly contribute to long COVID🧵
This is an important shift in understanding. It’s not just that T cells stay activated - the key question is why.
The new study shows that the drivers are homeostatic cytokines that normally help rebuild the T-cell pool after infection.
The new study shows that the drivers are homeostatic cytokines that normally help rebuild the T-cell pool after infection.
The problem is that COVID causes a major loss of T cells (lymphopenia).
The body responds by ramping up IL-7 and IL-15 to help replenish them.
But these cytokines become so abundant that T cells remain on standby for months - even long after the virus has cleared from the airways.
The body responds by ramping up IL-7 and IL-15 to help replenish them.
But these cytokines become so abundant that T cells remain on standby for months - even long after the virus has cleared from the airways.
This leads to a prolonged increase in CD25 and CD122 and a decrease in CD127.
In simple terms. T cells receptors get reprogrammed to stay more reactive and slower to return to their resting state!
That’s a measurable signature of chronic immune activation.
In simple terms. T cells receptors get reprogrammed to stay more reactive and slower to return to their resting state!
That’s a measurable signature of chronic immune activation.
And here’s the striking part.
It’s not only SARS-CoV-2-specific T cells that stay activated.
Bystander T cells - like those targeting EBV or influenza - show the same shift!
This means the issue isn’t persistent stimulation by viral antigen alone, but a global cytokine-driven dysregulation.
It’s not only SARS-CoV-2-specific T cells that stay activated.
Bystander T cells - like those targeting EBV or influenza - show the same shift!
This means the issue isn’t persistent stimulation by viral antigen alone, but a global cytokine-driven dysregulation.
This mechanism seems variant-agnostic. The disruption comes from the depth of lymphopenia and the intensity of the acute immune response.
Most people eventually normalize both T-cell numbers and receptor expression.
But the study shows that in a subset of patients, the abnormalities persist for 6–12 months.
This is not typical for other respiratory viruses.
But the study shows that in a subset of patients, the abnormalities persist for 6–12 months.
This is not typical for other respiratory viruses.
These individuals are also more likely to have ongoing symptoms.
Even 12 months later, they show higher CD25 on SARS-CoV-2-specific CD8 T cells
a hint that two processes may coexist
persistent viral antigens
long-term dysregulation of IL-7/IL-15 signaling.
Even 12 months later, they show higher CD25 on SARS-CoV-2-specific CD8 T cells
a hint that two processes may coexist
persistent viral antigens
long-term dysregulation of IL-7/IL-15 signaling.
Together, these factors create a state of low-grade chronic activation, T-cell fatigue, and impaired immune balance.
Mechanistically, this links acute COVID - immune instability - long COVID.
Mechanistically, this links acute COVID - immune instability - long COVID.
Why does this matter?
Because it finally identifies measurable biological mechanisms we can track - and potentially target
IL-15 signaling
dysregulated IL-7Rα
sustained CD25/CD122 elevation
delayed reconstitution of the T-cell pool!
Because it finally identifies measurable biological mechanisms we can track - and potentially target
IL-15 signaling
dysregulated IL-7Rα
sustained CD25/CD122 elevation
delayed reconstitution of the T-cell pool!
And it also explains why vaccination doesn’t reproduce this effect.
After an mRNA booster, receptor changes fade within 30 days and only affect antigen-specific cells - not the entire T-cell population!
After an mRNA booster, receptor changes fade within 30 days and only affect antigen-specific cells - not the entire T-cell population!
So, it’s an infection that can disrupt the fundamental regulatory system of T cells for months!
And this failure to return to immune equilibrium is one of the strongest mechanistic explanations for long COVID.
And this failure to return to immune equilibrium is one of the strongest mechanistic explanations for long COVID.
IL-7/IL-15 dysregulation is a central node that determines whether the immune system truly recovers or slips into chronic dysfunction.
This study is the one of first to map that mechanism in full.
This study is the one of first to map that mechanism in full.
Ceglarek et al., 2025. Dysregulation of homeostatic cytokine receptors drives prolonged T cell activation following acute SARS-CoV-2 infection in humans. Nature Communications. nature.com/articles/s4146…
Knowing that the T-cell regulatory system is disrupted is crucial because it determines how fast immunity recovers, how we respond to new infections, how much inflammation we generate, and whether T cells stay functional or burn out.
Key reasons this mechanism is important
Persistent antigen
If the immune system cannot switch off properly, even small amounts of residual viral protein can keep it activated.
This pattern repeatedly shows up in long COVID cohorts.
Persistent antigen
If the immune system cannot switch off properly, even small amounts of residual viral protein can keep it activated.
This pattern repeatedly shows up in long COVID cohorts.
Chronic activation/exhaustion
T cells that stay on for months begin to lose range and efficiency.
Their repertoire narrows and their responses weaken - a milder version of patterns seen in chronic viral infections.
T cells that stay on for months begin to lose range and efficiency.
Their repertoire narrows and their responses weaken - a milder version of patterns seen in chronic viral infections.
Increased susceptibility and autoimmune risk
A dysregulated T-cell environment can mean greater vulnerability to other infections, paradoxical hyper-reactivity, chronic low-grade inflammation, and a higher likelihood of autoimmune complications.
All of these are observed in subsets of long COVID patients.
A dysregulated T-cell environment can mean greater vulnerability to other infections, paradoxical hyper-reactivity, chronic low-grade inflammation, and a higher likelihood of autoimmune complications.
All of these are observed in subsets of long COVID patients.
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