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This is a blog post aimed to make technical scientific concepts more “digestible” for a lay audience. The work discussed is based on the research by Kusnadi et al., published in Science Immunology in January 2021. To read their work directly, please click here.

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It’s been over a year since the words lockdown, remote working, and stay-at-home became frequent in our conversations, and we have the global impact of the COVID-19 pandemic to thank for that.

Since then, we have applauded the efforts of fast-acting scientists and pharma in pumping out effective vaccines to help slow down transmission, but unfortunately, vaccine administration efforts have been inconsistent all over the world. Global herd immunity seems like a noble concept, but with conflicting policies and lack of organization among governments, it’s something that will be impossible to reach—at least in the short-term.

But those of us who have been vaccinated are incredibly lucky. Vaccines introduce biological material (based on an infectious agent) into the body to prompt a response from the immune system. If a vaccinated individual encounters the actual infectious agent in the future, their immune system should be able to recognize the foreign invader and prevent an infection from progressing. And of all the immune system’s key players, we have our lymphocytes—our T cells—to thank for this!

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In a previous blog post of mine, I described in general what CD8+ T cells are, but let’s recap:

T cells are born in the thymus (hence the “T” in their name) and primarily serve as “soldiers of the body”. If the body is under attack by foreign particles (often referred to as antigen), T cells are the main players in fighting off these particles to prevent damage in the body.

They are further categorized as “T helper” cells (CD4+) or “cytotoxic T” cells (CD8+). CD4 and CD8 are structures made out of carbohydrate and protein “blocks” and exist on the surface of T cells, giving off their identity. CD4+ and CD8+ T cells differ in how they interact with other cells in the immune system and foreign invaders.

So we know that vaccines can provide protection against viral infections like COVID-19 by introducing T cells to parts of a virus and priming them to recognize the virus in the future. But for those who were infected with COVID-19 directly, did the intensity of the symptoms they experienced alter their immune system at the cellular level?

A collaborative group of scientists out of San Diego, California and the United Kingdom believe this was something worth investigating, and went so far as to use advanced genetic sequencing techniques to conclude that when it comes to our immune system warriors—CD8+ T cells—the severity of COVID-19 symptoms could affect how these cells look and function. Their work was recently published in Science Immunology, a prestigious peer-reviewed journal in the immunology field.

Since CD8+ T cells are critical when it comes to vaccine effectiveness and understanding immunity, it would make sense to characterize how CD8+ T cells are affected by COVID-19 infection. Obviously at the time this study began, not much was known regarding this, or much about COVID-19 in general.

The authors used blood samples from healthy donors, COVID-19 patients that were not hospitalized (characterized as ‘mild disease’ patients), and those that were hospitalized (‘severe’ patients) to isolate peripheral blood mononuclear cells (PBMCs).

PBMCs hold the key players of the immune system—T cells, B cells, natural killer (NK) cells, and monocytes—and are characterized by their round nuclei. Isolating this layer from the peripheral blood makes it easier to analyze CD8+ T cells in particular.

To isolate CD8+ T cells from the PBMC samples of COVID-19 virus-affected patients, the authors used a “cell sorter” to specifically collect CD8+ T cells expressing CD137 and CD69. Both of these markers indicate CD8+ memory T cells that are activated and are ready for battle. Going back to my earlier post, tacking the word ‘memory‘ next to CD8+ T cells indicates that these cells have the ability to recognize and act against a foreign invader.

Interestingly, the expression of CD137 and CD69 was increased in CD8+ memory T cells derived from “severe” COVID-19 patients compared to “mild” COVID-19 patients, perhaps indicating that severe patients could have an increased protective response to COVID-19 antigens in a future encounter.

Even though the analysis becomes more complex as the paper continues (given the nature of genetics-based techniques), there is no need to feel intimidated. There are still key take-aways from the paper that even someone with a non-scientific background would appreciate.

Depending on the viral infection, CD8+ memory T cells can respond by activating a number of different genes that can help with fighting back at the infection. For example, COVID-19-reactive CD8+ memory T cells were observed to express genes associated with exhaustion, the production of molecules (cytokines) that assist with fighting off infections, and activating T cells.

“T cell exhaustion” is exactly what it says—when T cells lose their ability to fight off infections due to non-stop stimulation by a foreign invader, they tire out and do not function optimally in their normal defensive roles. A common marker of “exhaustion” is programmed cell death protein (PD-1) which T cells can express on their surface. The issue is that PD-1 is also involved in the activation of T cells, so like most things in biology, it’s not black and white—there needs to be a balance.

The authors knowing this utilized single cell transcriptomics, a process that allows us to examine all sorts of genes expressed by an individual cell, to see if there was more to characterizing exhausted T cells beyond what is seen at the surface level.

Ultimately, they found that CD8+ memory T cells reactive to COVID-19 expressed a number of genes associated with exhaustion, because of their connection to type 1 interferon signaling. This cell signaling pathway is associated with immune system regulation and has been noted by earlier studies to be linked to the development of exhaustion in T cells.

Although patients with mild disease had more exhausted CD8+ memory T cells compared to severe disease patients, the exhausted CD8+ memory T cells in severe patients showed an increase in the number of genes associated with toxicity and inflammation.

Even though we would see this as a “negative” attribute of severe infection, it was noted that those with severe disease had CD8+ memory T cells that could survive for a longer time, although whether this observation can provide long-term immunity still requires investigation.

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Given that this is a study involving live individuals, using PBMCs is the only way to go, even though the analysis can be limiting (we can’t exactly do lung biopsies willy-nilly!). Even with its limitations however, the overall study does bring valuable insight as to how CD8+ T cells are affected by mild vs. severe COVID-19 infection.

The authors were able to use techniques to isolate single CD8+ T cells reactive to COVID-19 and determine that although patients with mild disease have more CD8+ T cells that are exhausted, the exhausted CD8+ T cells that severe patients do have lean towards higher levels of toxicity and inflammation, despite these cells also exhibiting features of increased memory responses and survival…

Maybe in this case, quality does take precedence over quantity? It will be interesting to see if any follow-up studies are conducted based on the findings of this paper, as we still have so much to learn about COVID-19. Although I do think it’s safe to say the authors uncovered some interesting details on how COVID-19 infections impact our immune system’s essential soldiers.

This has certainly been a lot to digest, but it was a delicious meal of brain food to dive into!

Resources cited in this post:

1. Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8+ T cells – Science Immunology
2. PBMC Wikipedia Page
3. Understanding memory CD8+ T cells – Immunology Letters
4. Understanding How COVID-19 Vaccines Work – CDC
5. T Cell Exhaustion – Frontiers Research Topics