German Study Shockingly Discovers That SARS-CoV-2 Caused Complement Activation Induces Excessive CD16+ T Cells With Increased Cytotoxic Functions!
Source: COVID-19 Immunology - CD16+ T Cells Jan 03, 2022 3 years, 7 months, 2 weeks, 5 days, 16 hours, 36 minutes ago
COVID-19 Immunology: Researchers from Charité - Universitätsmedizin Berlin-Germany and the University of Bonn-Germany have in a new study discovered that SARS-CoV-2 caused complement activation induces excessive T Cell cytotoxicity especially in severe disease.
It has already been known that severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology. However, to date, it remains unclear whether T cells contribute to disease pathology.
The study team combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals.
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Shockingly, the study team identified highly activated, CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases.
It was found that the CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants.
These CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype.
The increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells.
Importantly the study findings showed that the proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.
The study findings were published in the peer reviewed journal:
https://www.sciencedirect.com/science/article/pii/S0092867421015622
Excessive T cell activation and altered phenotypes can contribute to infection-associated organ damage.
The study team provided evidence that SARS-CoV-2 infection in contrast to other acute and chronic infections promotes the formation of highly activated and proliferating HLADR+CD38hiCD137+CD69+ T helper cells and CD8+ T cells independent of disease severity, although this response occurred faster in severe COVID-19 patients.
More importantly, in severe COVID-19 patients, the study team detected differentiation of activated CD16+ T cells, which showed an increased immune complex-mediated cytotoxic potential and a potential to activate lung microvascular endothelial cells. Expanded clones within the CD16+ T cell compartment persisted and maintained their high cytotoxic potential.
The
COVID-19 Immunology study findings identified C3a as an upstream signal for the differentiation of the altered activated T cell phenotype. Proportions of activated CD16+ T cells and plasma complement protein abundance levels were associated with worse outcomes of patients with severe COVID-19. Thus, SARS-CoV-2-triggered complement activation creates an inflammatory milieu that drives differentiation of T cells with high immunopathogenic potential.
The study findings also showed that the increased C3a generation in severe COVID-19 patients promotes differentiation of CD16+ and also results in highly cytotoxic CD4+ and CD8+ T cells.
Interestingly, targeting distal complement effects by receptor blockade in a humanized preclinical model of SARS-CoV-2 infection prevented acute lung injury. Results from the first clinical trials on complement inhibition in COVID-19 also showed promising effects resulting in reduced inflammation and faster normalization of neutrophil and lymphocyte counts. In this context, C3 inhibition enabled a broader and better therapeutic potential as compared to C5 neutralization.
In all, it should be noted that this SARS-Cov-2 caused complement activation that induces excessive CD16+ T Cells with increased cytotoxic functions is a unique manifestation never seen in any disease so far and validates that fact that the SARS-CoV-2 coronavirus disrupts the human immune system in multiple of ways. Furthermore, there might also be implications for Long COVID as well but this warrants further studies.
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