Kyle Burrows, Ph.D. Candidate, Biomedical Research Centre, University of British Columbia

Defining Mechanisms Controlling Mucosal Inflammation: T Cells and ILCs
Kyle Burrows

Kyle Burrows received his BSc from the University of British Columbia. His current graduate research in Dr. Colby Zaph's lab is aimed to investigate the molecular mechanisms that regulate CD4 + T cell subsets and innate lymphoid cells (ILCs) in mucosal sites. The research at Colby Zaph's lab is focused on defining the cellular and molecular mechanisms controlling mucosal inflammation in the intestine and the lung. The Zaph lab utilizes animal models to investigate how perturbations in these mechanisms can result in diseases such as food allergies, inflammatory bowel disease (IBD) and asthma.


Topics:

  • Role and regulation of Th17 cells in mucosal sites
  • Analysis and role of Innate Lymphoid Cells (ILCs) in mucosal immunity

The Scientist

1. What made you choose scientific research as a career path?

I decided to choose scientific research by going through a co-op at UBC. During undergrad, I was able to go out to the workforce and work a few different jobs for a couple of months to get a feel for what I wanted to do. I worked at an academic research lab and found the work challenging, but stimulating and rewarding, so I decided that that is probably the career for me.


2. What do you enjoy the most about research?

The thing I enjoy most about research is the challenge. There is no easy way to do research. It takes a lot of hard work and a lot of commitment. I really like the challenge, and enjoy it when you do have a breakthrough and you make new discoveries. It is a great feeling to have.


3. Who is your scientific idol?

I don’t think I have a scientific idol per say, there is quite a few people in the field that I really respect, like David Artis or Ruslan Medzhitov, who have made some great discoveries in immunology. I would really like to emulate my career after them.


4. What is your role in the Zaph lab?

In the Zaph lab, I'm a graduate student. I have my own independent research, which is focused on mucosal immune regulation. I am interested in immune cells at the barrier surfaces such as the lung and the gut, specifically, CD4+ T cells and innate lymphoid cells (ILCs). These cells are quite interesting because they have to rapidly respond to pathogens such as viruses, bacteria or helminths, but also tolerate the commensal bacteria and innocuous food antigens in the gut.

The Science

1. What have you found so far?

Previous research has shown that retinoic acid (RA) is important for both initiating T cell responses to pathogens, as well as promoting tolerance in the gut. My research is looking at different mechanisms that are influenced by RA, and what we found was a novel transcription factor that is only expressed in T cells located in the small intestine or T cells that are treated with exogenous RA. Interestingly, when we knock this molecule out or inhibit it in T cells, we find that cytokine production is altered, and in doing so, we are able to prevent disease progression in different animal models of colitis.


2. Does this novel transcription factor differentially affect the various subsets of T cells?

We find that it has an affect on Th17 cells. When we inhibit this transcription factor, it seems to allow T cells to produce a lot more IL-17 and IL-10, so it seems to promote barrier functions and immunoregulatory molecules. We think that is how it is protecting from disease progression in colitis.

Lots of evidence in the literature show that IL-17 both has a pro-inflammatory and an anti-inflammatory effect. IL-17 is known to mediate protection from extracellular pathogens such as fungi, but it has also been shown to promote intestinal epithelial cells to have stronger, tighter junction and promote barrier function, so that bacterial cells cannot cross the epithelial surface and induce inflammation.


3. What do you consider to be the most significant advancement in the field in the last 5 years?

I think a very hot topic right now is innate lymphoid cells (ILCs). They were discovered not too long ago, about 5 years, and research with them has just exploded. They were originally discovered as a single subset, but now there are multiple subsets: ILC1s, ILC2s and ILC3s, and they have very different functions. ILC2s in the lung are very important for inducing airway inflammation in response to antigens. You have ILC3s that are important for microbial defenses as well as regulating responses against commensal bacteria. There is a lot of research focusing on ILCs right now, and it is only going to expand in the future.


4. What is the main technical challenge in the field?

I think the main technical challenge in the field right now is with the characterization of innate lymphoid cells, because they are such a rare population, they don't have a good marker, like T cell receptors on T cells, it is hard to identify these cells in vivo. It involves a lot of different antibodies and a lot of staining. I think there needs to be a new way to identify these cells. A tool like the CyTOF may help in the future once they start being more common in laboratories, but right now I would say we're pretty limited in our staining capabilities to identify these rare subsets.

It's quite difficult to isolate ILCs right now because they're so rare. If there was definitely a faster and easier way to sort ILCs, it would be a great advantage to my research. Especially because sorting takes so long, cells are usually sitting in the machine for a long time and you end up getting a lot of dead cells. A way to increase viability, say with magnetic sorting, would be definitely beneficial to research.

Request a free Innate Lymphoid Cells (ILCs) wallchart.

EasySep™

1. Why do you use EasySep™?

I've been using EasySep™ pretty much since the beginning of my grad school career, so it's probably been about 4 years now. We use EasySep™ because it is a very quick and easy method for isolating CD4+ T cells from spleens and lymph nodes. I've used it for CD8+ T cells in the past as well. We can quickly isolate T cells in high purity and great viability in order to culture them in vitro or do further analysis, like chromogen IP or RNA sequencing. We have great purities, so EasySep™ works great for these isolations and analyses.


2. How does EasySep™ enable your research?

I think EasySep™ helps my research because it is very quick and easy, so it is a great way to isolate cells fast in order to get a pure population that has great viability. We do not have to worry about any of the cells getting lost.


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STEMCELL's Scientific Summaries

On the role and regulation of Th17 cells in mucosal immunity

CD4+ T cell subsets such as Th17 cells and the regulatory T cells (Tregs) play critical roles in maintaining mucosal immune homeostasis, where immune regulation is critical to prevent unnecessary immune responses toward commensal and food antigens. Th17 cells are commonly known as a pro-inflammatory cell type with harmful effects in autoimmune diseases; however, Th17 cells have been suggested to play a dual role in mucosal immunity1. Many studies have shown that Th17 cells induce inflammation to promote the pathogenesis of diseases affecting mucosal sites, such as the gut2 and the lung3. On the other hand, some studies have reported that IL-17 has protective effects in diseases, including asthma4. Whether these protective IL-17 cytokines are truly derived from Th17 cells is uncertain. The ability modulate T cell subsets, including Th17, remains a key topic of research. Earlier studies have revealed a key role for the vitamin A metabolite retinoic acid (RA), which can promote the induction of Tregs and suppress Th17 responses5,6. With many immune-modulatory molecules being proposed as potential therapies, it will be interesting to determine how these molecules affect the multiple roles of IL-17 cytokines in vivo.


On the analysis and role of Innate Lymphoid Cells (ILCs) in mucosal immunity

Over the past 5 years, ILCs have been defined as a new arm of innate immunity, and have gained tremendous popularity. ILCs are characterized by the lack of cell surface markers that define other immune cell lineages (Lin-), making them difficult to isolate and analyze7. These cells do not possess any antigen specific receptors; however, like T cells, they commonly express CD25 and CD127. ILCs can be divided into 3 major groups: T-bet+ ILC1, which express IFN-γ, GATA-3+ ILC2, which secrete IL-4, IL-5 and IL-13 and RORγt+ ILC3, which can secrete IL-17A7. These groups of ILCs can be distinguished by their expression of different cytokine receptors. For example, ILC2s express the IL-33 receptor, whereas ILC3s express the IL-23 receptor8. Recently, the role of ILCs have been highlighted in mucosal immunity: ILC2s play a critical role in the development of allergy9 and ILC3s are involved in the pathogenesis of inflammatory bowel disease10. Although the basic biology of ILCs are already being intensely studied, how these findings can be applied to translational research in diseases affecting mucosal sites will be an exciting avenue of future research.

References

  1. O’Connor W et al. (2010) The dual nature of T(H)17 cells: shifting the focus to function. Nat Immunol 11(6): 471–476.
  2. Feng T et al. (2011) Th17 cells induce colitis and promote Th1 cell responses through IL-17 induction of innate IL-12 and IL-23 production. J Immunol 186 (11 ): 6313–6318.
  3. Zhao J et al. (2013) Th17 responses in chronic allergic airway inflammation abrogate regulatory T-cell-mediated tolerance and contribute to airway remodeling. Mucosal Immunol 6(2): 335–346.
  4. Schnyder-Candrian S et al. (2006) Interleukin-17 is a negative regulator of established allergic asthma. J Exp Med 203 (12 ): 2715–2725.
  5. Mucida D et al. (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Sci 317(5835): 256–260.
  6. Hall JA et al. (2011) The role of retinoic acid in tolerance and immunity. Immunity 35(1): 13–22.
  7. Artis D & Spits H. (2015) The biology of innate lymphoid cells. Nature 517(7534): 293–301.
  8. Spits H et al. (2013) Innate lymphoid cells--a proposal for uniform nomenclature. Nat Rev Immunol 13(2): 145–149.
  9. Halim TYF et al. (2014) Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40(3): 425–435.
  10. Eken A et al. (2014) IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism. Mucosal Immunol 7(1): 143–154.