Normally, the months of September and October are dotted with important dates—end of summer barbeques, the first day of school, joyful plans for Halloween and excitement for the upcoming Holiday Season. This year is different though; barbeques are smaller and are done virtually over Zoom, the first day of school meant logging into a virtual classroom, and holidays plans are being downsized or canceled. And while some folks were able to ‘turn their brains off’ over the summer and take time off during the vacation season, scientists around the world were working full tilt to understand the new coronavirus, SARS-CoV-2, and the subsequent COVID-19 disease. In this Fall blogpost, we highlight a few T cell specific publications (two reviews and two reports) to get up to speed on the latest findings.
The first review article, “SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection”[i] was published in July 2020. This review concisely summarizes what has been learned since January 2020, focusing on T cells and the unknowns surrounding their activity in response to COVID-19. There was so much uncertainty in the beginning—why were some people hospitalized while others were asymptomatic? In examining cases of lymphopenia, it was hard to tell where all the T cells had gone; were they exhausted and eliminated or sequestered in tissues? Cytokine storms started appearing in some patients but not in others, and while scientists were starting to identify antigenic proteins, antibody persistence seemed to be short-lived. Many of us came into the summer doubting the development of a successful vaccine within the next two years.
One panicky popular comment you hear from talking heads on tv is: “I heard that COVID-19 antibodies don’t last long. Does this mean we’ll keep getting infected over and over?” And the response was, “Yes and maybe?” It sounds scary at first but imagine this—if our bodies were “fully stocked” with antibodies against every immune challenge we’ve ever had, our blood would be sludge. And that is even less practical than hoarding toilet paper. Enter memory T cells: they remember previous immune challenges and supply antibodies when needed, like a prepaid subscription delivered on-demand.
It was heartening to read the article: “Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19”[ii]. This article examines expression of T cell markers in healthy blood donors, convalescent individuals, and patients with moderate or severe COVID-19. There is a notable difference in CD4+ and CD8+ markers between healthy and convalescent groups versus the moderate/severe group, suggesting a way to identify a robust immune response to infection. From there, the authors noted unusually high levels of CD38 consistent with memory CD8+ T cells from the moderate/severely infected individuals. Additionally, the emergence of memory SARS-CoV-2 specific CD8+ T cells correlated strongly with the number of symptom-free days after infection, indicating the successful generation of memory T cells. Finally, the team challenged convalescent individuals, exposed family members, and healthy blood donors with COVID-19 spike, membrane, and nucleocapsid peptide sets and saw antibody reactions in the CD8+ and CD4+ T cells compartments in all three groups. While the highest responses were seen in the convalescent groups, it is promising to note the significant levels of circulating antibody response in exposed family members and healthy blood donors.
One concern that arose over the summer was whether people could be repeatedly reinfected by the circulating coronavirus. If reinfection was possible, could there ever be any hope of reaching herd immunity? By the time of the next article’s publication in August 2020, over 19 million people were confirmed to have been infected with COVID-19, the majority of whom did not require hospitalization. Now consider the unknown number of people who experienced a mild bout of “flu-like symptoms” and were not diagnosed. If the memory T and B cells in these individuals can maintain a resistance to COVID-19 upon subsequent challenge, then the likelihood of herd immunity and decreased transmission rates become possible.
The paper “Functional SARS-CoV-2-specific immune memory persists after mild COVID-19”[iii] examines the efficacy of memory cells after mild COVID infection. In this study, “mild” is defined as low-level symptoms lasting around thirteen days, no hospitalization, and COVID-positive determination by a PCR nasal swab. Memory T and B cells work together to generate antibodies upon reinfection. Samples from COVID-19 infected donors were examined 86 days post-symptom onset to determine if, and to what extent, memory lymphocytes were present. By this time, the inflammatory response due to the infection had subsided and the donors were in an early phase of immune memory. In cell-free competition assays, plasma from COVID-positive donors was compared to healthy donor plasma for the ability to neutralize binding reactions to the COVID spike protein receptor binding domain. COVID-positive donor plasma was more neutralizing than healthy donors, indicating the persistence of IgG antibodies for at least three months after symptom onset. Following that, the group measured the proportion and number of receptor binding domain-specific memory B cells and found that these cells were enriched in the COVID-positive populations as opposed to the healthy controls. Additionally, SARS-CoV-2-specific memory CD8+ and CD4+ T cells were present and maintained the ability to signal the memory B cells, spurring them to action. Finally, the group randomly selected seven neutralizing antibodies to be cloned and expressed as IgG monoclonal antibodies. Overall, 50% of these monoclonal antibodies demonstrated inhibitory activity, indicating protection from subsequent reinfection.
Additional new information from the summer is well reviewed in “T cell responses in patients with COVID-19”[iv]. This article highlights what has been learned about lymphopenia, CD8+ and CD4+ T cells, and illustrates a model of T cell activation in response to either mild or severe disease. There are clear differences in the immune response with respect to T cell number and clonality, cytokines and chemokines, and signaling molecules such as PD1, CD38, ICOS, and TIM3; all of which need to be characterized in future studies. In addition, how a patient’s viral load acts as an initial input signal to direct the severity of the immune response is still unknown. More attention has also been paid to the impacts of comorbidities such as age, blood type, cardiovascular health, and obesity, all of which present new areas of investigation and subsequent therapeutic interventions. Finally, the importance of memory T cells is again highlighted as we look for new signs of protective immunity against reinfection.
We are far from being out of the woods, and the cold season is fast approaching with its load of flu and probably more COVID-19. While we are impatiently waiting on a vaccine, we at NanoString want to extend our heartfelt thanks to all the researchers for their tireless efforts to learn more about COVID so that one day we can all go back to school, barbeques, and holiday family gatherings, and save a few trees from being turned into unneeded toilet paper. We truly appreciate you!
FOR RESEARCH USE ONLY. Not for Use in Diagnostic Procedures
[i] Altmann DM, Boyton RJ. SARS-CoV-2 T cell immunity: Specificity, function, durability, and role in protection. Sci Immunol. 2020;5(49):eabd6160. doi:10.1126/sciimmunol.abd6160
[ii] Sekine, T., Perez-Potti, A., Rivera-Ballesteros, O., Strålin, K., Gorin, J.-B., Olsson, A., Llewellyn-Lacey, S., Kamal, H., Bogdanovic, G., Muschiol, S., Wullimann, D.J., Kammann, T., Emgård, J., Parrot, T., Folkesson, E., Rooyackers, O., Eriksson, L.I., Henter, J.-I., Sönnerborg, A., Allander, T., Albert, J., Nielsen, M., Klingström, J., Gredmark-Russ, S., Björkström, N.K., Sandberg, J.K., Price, D.A., Ljunggren, H.-G., Aleman, S., Buggert, M., Karolinska COVID-19 Study Group, Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19, Cell (2020), doi: https:// doi.org/10.1016/j.cell.2020.08.017.
[iii] Pepper M, Rodda L, Netland J, et al. Functional SARS-CoV-2-specific immune memory persists after mild COVID-19. Preprint. Res Sq. 2020;rs.3.rs-57112. Published 2020 Aug 13. doi:10.21203/rs.3.rs-57112/v1
[iv] Chen Z, John Wherry E. T cell responses in patients with COVID-19. Nat Rev Immunol. 2020;20(9):529-536. doi:10.1038/s41577-020-0402-6