Thread by @ZdenekVrozina

Even three years post-infection, a subset of COVID survivors shows a persistently altered immune landscape, marked by elevated cytokines and incomplete recovery of key immune cell populations.🧵

Some inflammatory signals remain elevated, and certain immune cell populations never normalize. The strongest and most consistent changes involve the T-cell compartment rather than innate immune cells.

The authors describe the pattern as resembling immunosenescence because
naive CD4 and CD8 T cells - the reserve needed to respond to new infections - remain persistently reduced.

This is a hallmark of aging immune systems.
What this likely means biologically?
Reduced adaptive flexibility
Greater tendency toward chronic inflammatory activation
Less efficient immune reset after infection

At first glance - immune aging. Their immune profile resembles what we normally see in older individuals.

Early after infection, inflammation was driven mainly by monocytes.
However, by 2-3 years post-infection, those innate immune abnormalities largely normalized.
At that point, the persistent inflammatory state appears to be maintained primarily by T cells, especially Th17 subsets.

This represents a transition from an acute innate immune response to a chronic adaptive immune dysregulation.

Th17 cells normally play protective roles at epithelial barriers.
But when chronically activated, they are strongly associated with -
Persistent tissue inflammation
Autoimmune-like phenotypes
Ongoing immune activation even without active infection

In simple terms. Th17 responses are useful in acute defense, but harmful when they fail to shut off.

The most important finding.
The study identifies two functionally different Th17 subsets.

Pathogenic LTB+ Th17 cells
Strong pro-inflammatory gene expression, positive correlation with inflammatory cytokines, association with long-COVID symptoms such as pain, smell disturbances, and neuropsychiatric complaints

They may act as a biological bridge between persistent immune activation and clinical symptoms.

RORC+ Th17 cells - potentially regulatory
Negative correlation with inflammatory cytokines
Features suggesting a counter-inflammatory or compensatory role
They may represent an attempt by the immune system to restore balance.

The study finds long-term elevation of two important inflammatory mediators.
S100A8 (alarmin) - signals ongoing tissue stress or damage
IL-16 - attracts and activates CD4 T cells
These molecules likely create an environment that sustains pathogenic Th17 populations even years after infection.

The cohort size is moderate (47).
Measurements are from peripheral blood, not tissues.
Associations with symptoms are correlations

It involved the virus circulating at the very beginning of the pandemic, and the patients were hospitalized.
So the study essentially shows what long-term immunity looks like after the first pandemic wave.

But - the mechanisms described in the study
Th17-driven chronic inflammation
reduced naive T-cell reserves
persistent alarmin signals
are not specific to a particular variant, but rather appear to be linked to the severity and systemic intensity of the infection.

Sum:
COVID-19 can leave behind long-lasting immune remodeling, characterized by
Chronic low-grade inflammation
Persistent T-cell dysregulation
Reduced naive T-cell reserves
A sustained Th17-dominant inflammatory environment
This pattern resembles a state of premature immune aging combined with chronic immune activation.

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

The immune pattern seen years after COVID has striking parallels with other conditions.
Premature immune aging (loss of naive T cells)
chronic viral infections like HIV/CMV (persistent activation)
autoimmune diseases driven by Th17 inflammation
It reflects long-term immune remodeling.

In essence, the immune system appears to shift from an acute response into a chronic dysregulated state.
This is best described as persistent immune dysregulation!