Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2

No, this is not a pre-print about T cell dysregulation due to SARS-COV-2. It compares 27 people with LongCOVID (LC) to 16 controls and observe there is more immune activation in LC patients. The interpretation and context of the results are provided below.

​All data are from the pre-print unless otherwise mentioned. 

​The cohort is from the first C19 waves; no vaccines.
The authors find difference in LC patients (n=27) in T cell subset distribution in ways that imply ongoing immune responses, as well as by sex-specific perturbations.

Please do interpret this correctly!
The graphical abstract:

LC patients show an increased frequency of CD4+ T cells poised to migrate to inflamed tissues (chemokine receptor expression level; see below). The authors claim to observe "exhausted" SARS-CoV-2-specific CD8+ T cells, and detect higher levels of SARS-CoV-2 antibodies. All this strongly suggests there is ongoing immune activation in LC patients.

Important: The numbers of T cells and cytokines in blood are similar between controls and LC patients:

When looking at all (total) CD4 T cells, there are some minor differences: More central memory T cells, more circulating follicular helper T cells and regulator T cells are found in LC patients blood.

This is however not observed in the SARS-CoV-2-specific CD4 response in the blood: i.e. in only those CD4 T cells that are specific for proteins of SARS-CoV-2. This at first sight suggests that in most of these 27 patients, extended SARS-CoV-2 infection itself may not be the predominant cause of the activated immune phenotype.

However, a closer look within the SARS-CoV-2 specific CD4 T cells suggests there may be an effect from a longer infection period. There are some very specific differences: increased expression of some chemokine receptors. This includes CXCR5, which is important for the interaction between T and B cells and entry in the germinal centres where B cells are instructed to make antibodies and mature their antibodies. CXCR4 and CCR6 are involved in recruitment and migration to places of inflammation and mediate cell-cell interactions. However; note that these are relative subtle differences.

In the CD8 T cell subset, there are no general differences in the total population of T cells. But in the SARS-CoV-2 specific CD8 T cells there are some differences in activation markers. The authors may call this "exhaustion", but there is no functional evidence for that conclusion. This seems a strong statement that is not backed up with the data shown. I would think that these cells are likely to respond fine when tested, Additional data seems to suggest this is the case. 

Why is it not sufficient to make claims about T cell exhaustion with the data the authors show?

A great example why functional data is important to claim exhaustion is that these same markers also indicate activation, even when cells are restimulated for 51x over 10 years (mouse). The markers often used to indicate potential exhaustion; PD-1, TIM-3, etc, are highly expressed by these cells, yet, they perform their functions fine. These same markers are also indicative of T cell activation.

-In LC patients there is an enhanced immune activity. It can have many causes: longer presence of SARS-CoV-2, reactivation of herpes viruses, reduced IFN responses, problems with cleaning up debris, etc. This we need to understand. In some there is a increase in IL-6: inflammation.

-Again not a manuscript that shows T cell dysfunction caused by SARS-CoV-2; these are LC patients and there will be an underlying reason for some perturbations. -It also does not show T cell exhaustion; there are no functional data that support this. Cytokine production is fine!

-It does show good T cell numbers, CD4 and CD8 (NO T cell depletion), and good functional T cell responses. There are subtle differences, measurable, that could be meaningful: but we do not know cause and effect.

-Remember this is in LC patients only and should not be applied to the whole population.