23-29 november 2020
The activation of T-cells against SARS-CoV-2 does not allow patients to be saved
A team of researchers recently tried to understand in detail the T-cell immune response to the virus. It must be remembered that the elimination of a virus by the organism requires an effective immune system response specifically directed against the viral proteins and orchestrated by the T-cells.
There are 2 types of T-cells:
- The CD4+ T-cells that enable the activation of other cells within the immune system via the secretion of cytokines and interleukin.
- The CD8+ T-cells that enable the elimination of pathogens or infected cells.
T-cells are important for protective immunity, a crucial element in the development of vaccines. However, antigen-specific T-cells can also contribute to immune system complications (hyperinflammation). This is the principal cause of critical cases of COVID-19, as proved by the effectiveness of immunosuppressants against the illness.
When infection by SARS-CoV-2 takes place, the T-cell protective response is triggered by particular cells, antigen-presenting cells (APCs, such as dendritic cells) that allow contact between the viral proteins (antigens) and the immune system cells.
The immune response is directed specifically against certain proteins within the virus. To understand this process, it’s important to bear in mind that from a structural point of view, SARS-CoV-2 is made up of 4 proteins: the Spike protein (S), the envelope protein (E), the membrane protein (M) and the nucleocapsid protein (N). The S protein is on the surface of the viral particle and enables the virus to enter the cells via the ACE2 cellular receptor. It has been shown that patients who recover from COVID-19 have developed neutralizing antibodies directed against the S protein, blocking the interaction of the viral particle with the host cell, and therefore the entry of the virus into the cell. This highly specific humoral response only takes place due to the specific activation of T-cells against the S protein.
A new study is intended to identify, characterize and compare T-cell activation against the S,M and N viral proteins in patients at different clinical stages of the illness, during the acute phase and after recovery.
For the purposes of this study, 65 blood samples were analysed, from 7 patients considered to be in a moderate stage of the illness, 9 patients at a severe stage and 12 patients at a critical stage. In addition, 10 samples were analysed from patients who hadn’t been exposed to SARS-CoV-2 (these samples were taken before the pandemic). The blood cells of these patients (the T, B, and NK lymphocytes and the monocytes) were collected and incubated for 16 hours with mixed fragments of the S,M and N proteins, with a view to activating the T-cells using the APCs.
What are this study’s conclusions?
Firstly, the 3 proteins (S, M and N) have the ability to induce a response in the T CD4+ et CD8+ lymphocytes. The T CD4+ lymphocytes reacted in 96% of patients, and the T CD8+ lymphocytes in 75% of patients. The reactivity of the T CD4+ lymphocytes can be seen to be greater than the reactivity of the T CD8+ lymphocytes, which confirms the results of another study.
Next, the response of the T-cells specifically targeting SARS-CoV-2 in patients at the critical phase of the illness is as important as that seen in patients at the moderate phase: the amount of active T-cells is the same, and there is the same expression of interferon and cytokines. Likewise, there is a similar number of CD4+ and CD8+ memory T-cells in patients both at the critical phase and at the moderate stage.
In addition, T-cells are capable of cross-neutralisation against the virus, but at a lower rate, for 3 out of the 10 patients not exposed to Sars-CoV-2, demonstrating a pre-existing immunity. This pre-existing immunity is probably due to previous infection by other seasonal coronaviruses that cause colds in particular. This cross-reactivity may also explain the hyper-reactivity of the T-cells that leads to acute inflammation at critical stages of the illness.
Finally, the study compares the T-cell response in two sets of patients: those having eliminated the virus and the others not. 11 people were included from the group of patients who had got rid of the virus and 7 patients where elimination had not occurred. No significant difference was observed in terms of the T-cell response between the 2 groups. The extent and the functioning of the T-cell response are comparable before and after elimination of the virus in patients at the critical stage of the disease.Strangely, higher levels of neutralizing antibodies targeting the SARS-CoV2 virus were found in patients who had not eliminated the virus compared to those who had. It may be suggested that those antibodies which prevent the virus from entering cells lead to greater numbers of free viruses in the extracellular space. However this theory needs further study on a larger group of patients.