University of Pennsylvania Scientist Dispels Fallacies and Fake News Generated About Effectiveness Of T-Cells To Combat SARS-CoV-2 After Vaccine Failures!

T Cells-SARS-CoV-2: Researchers from one of the few last unblemished and credible research institutions in the USA, ie the Perelman School of Medicine, University of Pennsylvania have published a detailed report in the peer reviewed journal: Nature Reviews Immunology, detailing carefully curated past published study findings and existing evidence about suboptimal, excessive or otherwise inappropriate T cell responses associated with SARS-CoV-2 infections versus their claimed roles in the resolution of COVID-19 as well as their claimed potential to provide long-term protection from reinfection with SARS-CoV-2, dispelling many fake news and published manipulated study findings in the last few weeks about effectiveness of T Cells and cross-reactive T cells in combating SARS-CoV-2 and its variants including Omicron that were generated to cause more deflections away from the main issues that the existing COVID-19 vaccines are failing miserably!
https://www.nature.com/articles/s41577-020-0402-6
 


The medical scientists from  Institute for Immunology-University of Pennsylvania in their report highlighted some of the key observations made for conventional αβ CD8+ and CD4+ T cells in COVID-19, including the prominent lymphopenia observed in patients with severe disease, relevant features of CD8+ versus CD4+ T cell responses in patients who are hospitalized, features of T cell differentiation that may be altered and current data on whether the overall magnitude of the T cell response in patients with COVID-19 is insufficient or excessive and how these features may relate to disease.
 
The T Cells-SARS-CoV-2 report also covered emerging data on SARS-CoV-2-specific T cells found in patients who have recovered from COVID-19 and the implications for T cell memory.
 
The report highlighted one key feature of SARS-CoV-2 infection which is lymphopenia. Lymphopenia is associated with severe disease but is reversed when patients recover. In some patients, lymphopenia has been reported to affect CD4+ T cells, CD8+ T cells, B cells and natural killer cells whereas other data suggest that SARS-CoV-2 infection has a preferential impact on CD8+ T cells.
 
Also, COVID-19-associated lymphopenia may be more severe or persistent seems to be more selective for T cell lineages. It is possible that the peripheral lymphopenia observed in patients with COVID-19 reflects recruitment of lymphocytes to the respiratory tract or adhesion to inflamed respiratory vascular endothelium.
 
A recent scRNA-seq analysis of the upper respiratory tract from patients with COVID-19 showed that there was a markedly decreased contribution of cytotoxic T lymphocytes in patients with severe disease compared with those with moderate disease. In severe disease, lymphopenia may be associated with high levels of IL-6, IL-10 or tumour necrosis factor (TNF), potentially through a direct effect of these cytokines on T cell populations and/or indirect effects via other cell types, such as dendritic cells and neutrophils.
 
It was also found that hyperactivation of T cells or high levels of expression of pro-apoptotic molecules, such as FAS (also known as CD95), TRAIL or caspase 3, could also contribute to T cell depletion.
 
Numerous past studies have reported alterations in the activation and/or differentiation status of CD8+ T cells in severe COVID-19. For example, there is evidence of terminally differentiated T cells or possibly exhausted T cells in severe disease, with reported increases in expression levels of the inhibitory receptors PD1, TIM3, LAG3, CTLA4, NKG2A and CD39. However, expression of these receptors could also reflect recent activation, and it is not clear whether the T cells in patients with COVID-19 are exhausted or just highly activated.
 
Similar to CD8+ T cells, there is evidence of functional impairment and increased expression of activation and/or exhaustion markers by CD4+ T cells in patients with COVID-19. Case reports have suggested that CD8+ T cell activation might be greater than CD4+ T cell activation, as defined by activation markers such as CD38 and HLA-DR. Lymphopenia also affects CD4+ T cells, although some studies suggest that the impact is less than that for CD8+ T cells. It remains to be determined how lymphopenia might relate to CD4+ T cell activation and/or dysfunction.
 
There is also evidence that hyperactivation or hypoactivation of T cells, or skewing towards an ineffective differentiation state (for example, TH17 cells, exhausted T cells or terminally differentiated T cells), might not be optimal in some patients with COVID-19. Several features that have been described in patients with severe COVID-19 - including high levels of systemic cytokines or chemokines, most notably IL-6, CXCL8, CXCL9 and CXCL10, or delayed or defective type I interferon responses could potentially skew T cell responses.
 
Though lymphopenia is not a unique feature of SARS-CoV-2 infection, it may be more prolonged in patients with COVID-19, and lymphopenia-induced proliferation can clearly affect T cell differentiation and activation; however, the contribution of lymphopenia to T cell differentiation in patients with COVID-19 has not yet been investigated.
 
It was also found that co-morbidities in COVID-19 patients could also affect T cell responses but the mechanisms behind those remains poorly understood. Causal associations may exist, perhaps connected to some of the underlying genetics. However, it is also possible that certain co-morbidities or pre-existing conditions make patients with severe disease less able to tolerate the severe virus-mediated and immune-mediated pathology associated with SARS-CoV-2 infection.
 
The scientists from University of Pennsylvania also questioned whether protective T cell memory can form following either SARS-CoV-2 infection or vaccination. Although data on vaccination will await trial results, early data from patients with COVID-19 who have recovered are promising. Memory CD4+ T cells and CD8+ T cells were detected in 100% and 70% of patients who recovered, respectively. Moreover, memory T cell responses were detected for multiple SARS-CoV-2 proteins, including not only spike protein but also nucleoprotein and membrane protein.
 
However, whether these T cells provide protective immunity is unclear, and addressing this question for T cells alone will be confounded by the presence of SARS-CoV-2-specific antibodies in patients who recover. Nevertheless, ongoing analysis of patients who have recovered should provide insights into the protective capacity of immune memory, including humoral and cellular memory, as these individuals are potentially re-exposed to SARS-CoV-2 in the community. Further studies should also define the differentiation state and durability of T cell memory. Moreover, defining how T cell memory forms in patients who experience mild symptoms of COVID-19 versus severe disease will be important. Although evidence of T cell memory to other coronaviruses is encouraging, such immune natural history studies for SARS-CoV-2 will likely be valuable for examining vaccine-induced T cell responses.
 
The study team University of Pennsylvania said that accumulating evidence supports a role for T cells in COVID-19 and probably in the immunological memory that forms following recovery from SARS-CoV-2 infection.
 
Most, although not all, patients who are hospitalized seem to mount both CD8+ and CD4+ T cell responses, and evidence points to possible suboptimal, excessive or otherwise inappropriate T cell responses associated with severe disease.
 
In reality, multiple distinct patterns of T cell response may exist in different patients, which suggests the possibility of distinct clinical approaches tailored to the particular immunotype of a specific patient.
 
The study team said that more carefully defining distinct classes of T cell response types in COVID-19 and delineating how pre-existing conditions, co-morbidities, race, ‘immune health’ status and other variables influence T cell responses should reveal novel opportunities for treatment and prevention.
 
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