Preprint: Increased migratory/activated CD8+ T cell and low avidity SARS-CoV-2 reactive cellular response, post-acute COVID-19 syndrome 2022 Paniskaki

[Andy]

Abstract

The role of autoimmunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although clinicians observe a growing population of convalescent COVID-19 patients with manifestation of post-acute sequelae of COVID-19. We analyzed the immune response in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors.

The phenotyping of lymphocytes showed a significantly higher number of CD8+ T cells expressing the Epstein-Barr virus induced G protein coupled receptor 2, chemokine receptor CXCR3 and C-C chemokine receptor type 5 playing an important role in inflammation and migration in PASC patients compared to controls. Additionally, a stronger, SARS-CoV-2 reactive CD8+ T cell response, characterized by IFNγ production and predominant TEMRA phenotype but low SARS-CoV-2 avidity was detected in PASC patients compared to controls. Furthermore, higher titers of several autoantibodies were detected among PASC patients.

Our data suggest that a persistent inflammatory response triggered by SARS-CoV-2 might be responsible for the observed sequelae in PASC patients. These results may have implications on future therapeutic strategies.

https://www.biorxiv.org/content/10.1101/2022.12.03.519007v1

 

[Hutan]

Additionally, a stronger, SARS-CoV-2 reactive CD8+ T cell response, characterized by IFNγ production and predominant TEMRA phenotype but low SARS-CoV-2 avidity was detected in PASC patients compared to controls.

Noting this.

The median age of the PASC study group was 51.5 years (range 19-68 years), whereas the control cohort was significantly younger, with a median age of 30 years (range 19-50 years, p=0.0002 two tailed unpaired t test). The PASC and control cohorts comprised of 63% (n=25) and 70% (n=10) female participants, respectively and showed no statistical gender difference (Fisher´s exact test, p<0.05). PASC patients (median BMI 29, range 17.6-52.5) showed significantly higher BMI compared to controls (median BMI 22, range 17.9-35) (Mann Whitney test, p=0.0003). All PASC study subjects suffered from at least two symptoms. The PASC study group presented significantly more comorbidities compared to the controls (unpaired t test p=0.0006).

The controls were not well matched - they were much younger, lower BMI, healthier in other respects.

Only 42.5% of the PASC reported fatigue. 70% had shortness of breath or exercise intolerance.

 

[wigglethemouse]

It looks like this paper was reviewed and published on 1 June, 2023 with a new title. Interesting that TEMRA came up again in Long Covid and was highlighted by Dr. Cliff's team at UCL in ME/CFS. Could there be something about TEMRA that is important to dig deeper on? Interesting that these cells can be activated WITHOUT TCR stimulation.

Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19, June 2023, Paniskaki

Abstract

The role of adaptive SARS-CoV-2 specific immunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although a growing population of convalescent COVID-19 patients with manifestation of PASC is observed.

We analyzed the SARS-CoV-2-specific immune response, via pseudovirus neutralizing assay and multiparametric flow cytometry in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors.

Although frequencies of SARS-CoV-2-reactive CD4+ T cells were similar between the studied cohorts, a stronger SARS-CoV-2 reactive CD8+ T cell response, characterized by IFNγ production and predominant TEMRA phenotype but low functional TCR avidity was detected in PASC patients compared to controls.

Of interest, high avidity SARS-CoV-2-reactive CD4+ and CD8+ T cells were comparable between the groups demonstrating sufficient cellular antiviral response in PASC. In line with the cellular immunity, neutralizing capacity in PASC patients was not inferior compared to controls.

In conclusion, our data suggest that PASC may be driven by an inflammatory response triggered by an expanded population of low avidity SARS-CoV-2 reactive pro-inflammatory CD8+ T cells. These pro-inflammatory T cells with TEMRA phenotype are known to be activated by a low or even without TCR stimulation and lead to a tissue damage. Further studies including animal models are required for a better understanding of underlying immunopathogensis. Summary: A CD8+ driven persistent inflammatory response triggered by SARS-CoV-2 may be responsible for the observed sequelae in PASC patients.

LINK | PDF | Frontiers in Microbiology

 

[wigglethemouse]

@Jonathan Edwards Could this paper be relevant for your QEIOS paper if there is another revision? i.e. increased IFN-gamma and a TEMRA T cell type that can be activated without TCR stimulation?

 

[Jonathan Edwards]

Yes, TEMRA would do I guess.

 

[jnmaciuch]

Just now noticing that 82% of PASC participants were labeled as obese compared to 20% of the controls, according to table 1. A 62% difference is pretty damning, especially for something already associated with abnormal PBMC findings

 

[wigglethemouse]

Just now noticing that 82% of PASC participants were labeled as obese compared to 20% of the controls, according to table 1. A 62% difference is pretty damning, especially for something already associated with abnormal PBMC findings

The updated paper did look at this. Here is Supplementary Table S2 referred to in the text talking about why they think there is no correlation for obesity/BMI with T cell frequencies. Be interested to hear what you think of this.