Gamma Delta T cells: The Unsung Heroes of Immunology

2021 Bio-Rad Science Writing Competition 3^rd Place

Katelyn is currently a 5th year PhD student in Microbiology and Immunology at the University of Miami, USA. She studies skin immunology, particularly the contributions of gamma delta T cells to the antibacterial response and wound healing. Her focus is determining how the antimicrobial protein Perforin-2 influences gamma delta T cell effector functions.

Katelyn impressed the judges with her exceptional grammar and style in this informative article and her enthusiasm for her PhD research really shone through to make it a very enjoyable read.

We are delighted to publish her entry below.

I like to think of gamma delta T cells as the underdogs of immunology. Because they’re so outnumbered by their more famous and well-characterized alpha beta T cell counterparts, including CD4⁺ helper and CD8⁺ cytotoxic T cells, they’re often overlooked by researchers. Alpha beta T cells are so potent that many assumed gamma delta T cell activities must be redundant, making them doomed for eventual extinction; however, research over the past decade has proven that there is more to these humble T cells than meets the eye.

When I first sat down with my PhD advisor to learn about her research interests, she regaled me with tales of gamma delta T cells’ critical contributions to the immune response against a vast array of diseases including malaria, tuberculosis, Listeria infections, and cancer. Even though gamma delta T cells only constitute about 1–5% of lymphocytes in the blood, they’re prevalent in epithelial tissues like the lungs, gut, reproductive tract, and skin. This positions them to act as first responders to tissue damage and infection (Nielsen et al. 2017).  

The focus of my PhD project has been investigating how gamma delta T cells interact with their bacterial neighbors in the skin. Researchers have discovered that skin-resident gamma delta T cells have a set of weapons, distinct from those wielded by alpha beta T cells, that make them efficient killers of pathogenic bacteria like Staphylococcus aureus. While alpha beta T cells can only recognize antigens that have been processed and presented by major histocompatibility complex (MHC) molecules, gamma delta T cells can use their T cell receptors to bind directly to microbial antigens independently of MHC molecules (Vantourout et al. 2014). This allows them to identify and respond to infections much more quickly than conventional T cells. But gamma delta T cells are also team players. Once they’ve become activated, they produce the cytokine IL-17A, which recruits neutrophils to the site of the infection where they ingest and kill bacteria through phagocytosis (Cho et al. 2010). Surprisingly, gamma delta T cells can also phagocytose bacteria — a trait previously unheard of in a T cell (Barisa et al. 2017, Zhu et al. 2016).    

It’s clear that gamma delta T cells pull their weight in the fight against pathogenic bacteria, but little is known about what happens when these cells interact with commensal bacteria — the friendly microbes that reside permanently on human skin but don’t cause disease. My lab wondered if antigens from “good” bacterial species, such as Staphylococcus epidermidis, might activate gamma delta T cells and help prepare them to fight off the bad bacteria when they arrive.

To explore this question, we used a well-characterized ex vivo skin infection model. This method consists of culturing pieces of human skin on gauze pads soaked with cell culture media and applying S. epidermidis to the skin surface. After collecting the skin pieces at different time points post-bacterial colonization and analyzing the frequency of various skin cell types using flow cytometry, we found that S. epidermidis-colonized skin had increased numbers of gamma delta T cells compared to control skin.  

Upon further analysis of the S. epidermidis-stimulated gamma delta T cells, we found that they had begun producing significantly increased amounts of a protein called Perforin-2. Perforin-2 is a recently discovered antimicrobial protein that pokes holes in bacterial cell membranes after the bacteria enter a mammalian cell, allowing toxic molecules like granzymes and reactive oxygen species to penetrate the bacterial cells and destroy them (McCormack et al. 2015). This led us to believe that Perforin-2 may be a new secret weapon in the gamma delta arsenal.  

To test this idea, we isolated human skin cells and infected them with methicillin resistant S. aureus (MRSA). One group of cells was pretreated with S. epidermidis for 24 hours prior to MRSA infection, while the other group was not. The gamma delta T cells that were pretreated with S. epidermidis showed higher Perforin-2 expression compared to the nonpretreated cells. These cells also killed significantly more MRSA cells, meaning Perforin-2 may contribute to the gamma delta T cell mediated antimicrobial response. We have recently published these results (Pastar et al. 2020) and hope to continue our studies to figure out how S. epidermidis activates Perforin-2 expression in gamma delta T cells and whether or not this pathway can be triggered by other species of commensal bacteria as well.

My research on gamma delta T cells has taught me that championing the underdog isn’t always easy. When studying a less characterized cell type, you’re inevitably going to have to do a lot of the grunt work when it comes to getting to know your cells: learning how to efficiently isolate them, keep them alive in culture, and measure their responses to immune challenges. For me, this meant countless hours toiling away in the lab, unsure if I was even a good enough scientist to get any of my experiments to work (hello, impostor syndrome!).

But I managed to persevere because I believed that the story of the gamma delta T cell is one that’s worth telling. If, through my struggles, I was able to bring to light one more of these enigmatic cells’ secrets, then all my efforts were worth it.