T Cell Types and Their Functions
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Computer animation
Transcript: English(auto-generated)
00:04
So, in my laboratory, we're interested in understanding the immune response to infection and cancer. In particular, we focus on T cells, and T cells are important because naive T cells are able to recognize antigens from virus-infected cells or tumor cells.
00:21
And in response to those antigens, they will undergo vigorous clonal expansion, where even a single naive T cell can turn into hundreds of thousands of cells over a few days. So after this vigorous clonal expansion, T cells will develop into activated effector cells. And these effector T cells are important because they are the ones that are directly responsible
00:40
for killing pathogen-infected cells or tumor cells. Now, after the infection is cleared or the tumor is controlled, what will happen is the vast majority of these effector T cells will die, and what will persist over the following weeks is a stable population of long-lived memory cells. And these long-lived memory T cells are important because should you become reinfected or should
01:01
your cancer come back, these long-lived memory T cells can respond again and turn into a population of secondary effector T cells, where they can kill the infected cell or the tumor cell, and the process will begin. So from the standpoint of human health and vaccination, effector cells are very important for directly controlling pathogens and tumors, and long-lived memory cells are important
01:24
for conferring long-lived protective immunity should you become reinfected or should your cancer come back. Now, with these vast changes in cell proliferation and dying off of the population of cells and the maintenance of quiescence and longevity in these memory T cells come
01:42
notable changes in metabolism. And these acquisition of different metabolic pathways in these cells is critical to not only afford their function, but also to promote their survival and their persistence. So in my laboratory, we're interested in understanding what are the metabolic requirements of effector T cells and memory T cells in hopes that we will reveal new targets
02:04
for the purposes of immunotherapy. To study what the different metabolic pathways were in effector T cells and memory T cells, we have to do a few things in the laboratory. First, we have to generate these different cell types, and we can do that by blending
02:21
both in vitro and in vivo approaches. And then once we actually have these cells isolated, we can start to look at their metabolism again in a variety of ways. One of the ways we can do this is measure aerobic glycolysis in these cells. Aerobic glycolysis is one ATP-generating pathway in these cells. And then we can also measure mitochondrial function in these cells, and in particular,
02:43
oxidative phosphorylation, which is another, the other, ATP-generating pathway in these cells. To try to begin to understand how those distinct metabolic phenotypes of those two pathways that exist in these cells relate to mitochondrial morphology, we can also use cells that have
03:02
green fluorescence mitochondria and then look at those mitochondria shapes on confocal by confocal microscopy, or we can actually look at the mitochondria at a deeper, more ultra-structural level by using electron microscopy. And we use these two different techniques within the paper to be able to understand how
03:20
mitochondrial morphology and metabolic pathway engagement was influencing the development of effector T cells and memory T cells. One of the most striking things that we observed was that effector T cells and memory T cells had completely distinct mitochondrial morphologies.
03:40
The effector T cells had round, punctate mitochondria and correlated with their ability to engage aerobic glycolysis, and the memory T cells had fused networks of mitochondria, and that correlated with their ability to use their mitochondria and oxidative phosphorylation. So what we did to answer the question as to whether or not were these punctate mitochondria
04:02
important for the generation of effector T cells, or were the fused mitochondria important for memory T cell development, one of the things we did was use the genetic model to remove the ability of the T cells to fuse their mitochondria, and then we could put them in an assay to test whether or not those T cells could still form memory.
04:22
And what we found is that when the T cells could not fuse their mitochondria, memory T cells could not form. So then to take that approach in the other direction, we could actually question, could we enforce fusion of the mitochondria, and would that actually allow us to make better memory T cells? We took that approach in vitro, and we enforced fusion of the mitochondria in T cells, and
04:46
then we could actually ask the question, did they form better memory T cells by using them in an anti-cancer model? And what we found after using those T cells in that model was that not only did we have better persistence of those T cells, is that they would also confer better protective
05:03
immunity against the cancer. These findings are relevant because they open up new possibilities of being able to modulate mitochondrial processes like fission infusion or other processes that may change the mitochondria morphologically, and that will allow us to target these new pathways
05:25
to alter immune cell function. So in thinking about where we take our research from here, we think about that in two ways. First, about how we're continuing the research in the laboratory.
05:40
And for now, we're actually looking at how these structural changes within the mitochondria and how different proteins expressed within these organelles influence structural changes that influence how the cells engage metabolic pathways. That's a big part of our ongoing research. But then in another way that we are continuing this line of research is actually trying
06:01
to collaborate with companies and other clinicians to be able to see if the things that we have found and others have found now in modulating metabolic pathways within immune cells, if we can actually translate this into humans and make better therapy.