Researchers have found peripheral T follicular helper cell responses to different structural proteins of SARS-CoV-2 and have studied how the response occurs over time.
Several studies of the SARS-CoV-2 virus infection, causing COVID-19, have reported how the human immune system responds to the infection. Many reports have found T-cell responses to the infection in almost all of the recovered patients.
Many of the current vaccine trials are using the presence of neutralizing antibodies as a measure of how efficient the vaccine is. Studies have found a correlation between neutralizing antibodies and protection from infection in non-human primates. Thus, understanding how T cells contribute to the formation of these antibodies is important.
However, it is challenging to direct study lymph tissues in humans, so peripheral T follicular cells (pTfh), or T follicular helper cells (Tfh) found in the blood, can help understand T cell responses.
There are only a few studies of pTfh for SARS-CoV-2. One study reported that the frequencies of pTfh increased in cases with severe infection. Upon testing deceased COVID-19 patients, another study found that Tfh response may be diminished in acute infections.
Although another study has shown a relation between SARS-CoV-2 spike protein-specific Tfh response and neutralizing antibodies, there are still many questions, such as if these responses contribute to the formation of antibodies and when after the infection these responses occur.
Protein-specific pTfh response
To further understand Tfh response in SARS-CoV-2 infection, researchers studied CD4 T-cell response to three structural virus proteins—membrane, spike, and nucleocapsid proteins—in 21 patients who had recovered from COVID-19. Of the 21 patients, 19 were confirmed to be positive, and although two did not test positive, they were in contact with a positive person and showed SARS-CoV-2 T-cell responses. The research is published on the preprint server medRxiv* in October 2020.
The authors measured the T cell response about 22 days and 30 days after onset of symptoms, during convalescent visits. They found about half the patients had CD4 T-cell response. They also found pTfh response, which is important in antibody response in 4 patients after 22 days.
At the first convalescent visit, the researchers found pTfh response to all the virus proteins, spike, membrane, and nucleocapsid. The spike protein response was strongly correlated to neutralizing antibodies. There was also a correlation between the membrane and nucleocapsid response and neutralizing antibodies, albeit at a lower level. This suggests pTfh response to the virus proteins may contribute to the development of neutralizing antibodies.
The low correlation of the pTfh response to the nucleocapsid protein might be because this protein is located inside the virus. In contrast, the spike and membrane proteins are on the outer surface of the virus. Thus, pTfh responses induced against the different virus proteins may not be equally effective in generating antibodies.
This supports the basis of many vaccines currently in testing, focusing on antibodies to the spike protein. However, as CD4 T cells' responses to different proteins may contribute to the formation of neutralizing antibodies, understanding them may be useful to more efficient vaccine designs. It is possible that the pTfh responses to the different proteins work together to form antibodies.
pTfh response is delayed in SARS-CoV-2 infection
The authors also tested to see when the pTfh develops in response to SARS-CoV-2 infection. The pTfh response was low during the first convalescent visit but increased with time and a robust response was detected during the second convalescent visit around 30 days after symptom onset.
About double the number of patients showed a response during the later visit compared to the first time. The delay in pTfh response in SARS-CoV-2 might be because of T-cell dysfunction, which has been reported before in many studies of the virus.
This observation is in contrast to those seen for other viruses like influenza, where responses were maximum seven days after vaccination or dengue, where the pTfh response decreased with time after infection.
The researchers used two flow cytometry-based tests for measuring the pTfh responses. But, the responses seen during the first visit were not always seen in the second visit. Using one test, they found responses in 57% of the patients in the first visit and 62% in the second visit. These are lower than those reported in other studies, where T-cell responses were seen in more than 80% of the cases.
The authors write this could be because of their stricter criteria for positivity, signals three times the background, based on other optimization studies.
Thus, the results of the study show pTfh responses are important in the formation of neutralizing antibodies to SARS-CoV-2, and understanding their response further could help design better prevention strategies.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.