Briefly ...The projects in our laboratory investigate how immune cells ensure host protection while avoiding autoimmunity. The problems we think about are largely in the area of cellular "decision-making". For example - How does a T cell know whether it's target is from a dangerous pathogen or the body's own cells ? How does it decide on what kind of response to make ? Once T cells initiate an assault, when and why do they decide to stop ? How do some T cells manage to stay around for long after an infection is resolved (and offer better protection if the pathogen should return) ?
While most of our studies focus on helper T cells, we are also interested in understanding how other tissues - and especially Dendritic cells - provide T cells with the necessary information and context for their decision-making. Details about specific projects can be found by following the links on the left. Below are some basic concepts to introduce you to the kind of work we do. .
At the first hint of trouble, our body typically mounts a rapid and rather blunt force defense against any perceived invading microbe. This is called the innate immune response. Although the innate response is extremely potent (and capable of preventing most pathogens from successfully colonizing our body) it has certain limitations. First, because it doesn’t care about the finer details of the precise pathogen that it is dealing with, it can be rather predictable. This can be an Achilles heel, since over time a pathogen can learn to evade this genomically hardwired response. Secondly, the innate response is usually unable to remember what it just did, for any reasonable length of time. So, when the same pathogen invades again, after a few years, the system will start from square one – rather than just repeat the section of the response that was most effective the last time. The evolution of the adaptive immune system provides a solution to both these problems – it is extremely specific in its activity and it retains a memory (often for a lifetime) of what it did best the last time around (to successfully defeat the pathogen). So rather than waste precious resources re-fighting the same battles from first principles, the adaptive immune system "improves" with each response – making the host less and less likely to suffer the same disease again. Indeed, this is one of the reasons why adults acquire lifelong immunity to many childhood pestilences… and why vaccination works!The problem is that, although we have known for a long time that the adaptive immune system is specific and has memory – we really don’t know enough to clinically manipulate it successfully (e.g. to make vaccines against any agent we want to or stop whichever autoimmune disease.. etc.). It is not that we don’t know anything about the adaptive immune system… in fact (thanks to decades of painstaking and creative experiments by many many labs) we now have a fairly good (but by no means complete) understanding of what it is made of. We know most of the cells that are part of the immune system. We know a lot about where these cells can be found and how they develop in the body. We know what quite a bit about the molecules they express and we even know how some of these molecules interact with each other. What we really have trouble with is figuring out how these cells actually operate. By "operate", here we are not referring to how they do the normal things that all cells routinely do (e.g. live, divide, move, etc.) - but how cells of the immune system identify the specific pathogen (e.g. versus the body's own cells), choose an appropriate course of action from many possible ones, know when to stop this course of action or remember it for a future battle. Clearly, there is an inherent logic that has also been evolved to accomplish such tasks (since the system can reproducibly execute such actions, many times and in most people) … but immunologists have only begun to scratch the surface of this complex evolutionary algorithm. In other words, a major challenge of our time is to decipher the software that has evolved to operate the hardware of the adaptive immune system.
Platform:Mus musculus - the laboratory mouse is the model of choice in our lab. Models serve an important role in laboratory research (although we do have projects focused on human cells or non-human primates). The choice of mouse as a model is widespread in Immunology Research. Well, using the same analogy above, the current version of the "control software" that we are looking at (in this analogy - the one running the human immune system) is incredibly complex. Over millions of years, this "software" has clearly been tweaked and modified ("improved"), in many evolutionary steps. However, without the luxury of evolutionary time and record to reexamine all of those small steps, scientists are forced to take an alternate approach. This approach is also analogous to a software engineer staring at a very complex code - trying to see what the whole thing does, by removing or editing small pieces and parts of it ... one at a time. This kind of an engineering approach can also be done in live animals - by molecular techniques of genetic engineering. So, we can now remove an essential gene or cell from an animal's immune system. Examining the consequence of that removal will then allow us to formulate new ideas or hypotheses about how the software actually works. In practical terms, this has involved using our distant cousins such as mice, rats … or even insects, to understand how their immune system operates.
What we do:Helper T cells are central players in the adaptive immune system. They not only directly participate in fighting infections and injury, but also help influence the decisions that other cells take in relation to a perceived threat. Aberrant activation of such T cells (e.g. against the body's own cells) can lead to diseases (e.g. autoimmunity) .. while failure to successfully activate them can result in poor protection against viruses, bacteria and parasites. We study how a helper T cell attempts to discriminate between things that it should not respond to (eg. healthy cells) versus things that it should (e.g. parasites and tumors). This falls under the umbrella of Tolerance and more details can be found under our projects on T cell tuning. We are also interested in the mechanisms that help T cells remember all the many diverse infections that they fought over the lifetime of the host. These projects on Memory build on our recent data suggesting that T cells organize themselves into colonies in the body, based on their shared interest in some of the body's own proteins. We are also looking into how cells from the innate immune system (Dendritic cells) communicate with T cells. This stems from a longstanding collaboration with Dr. Kaveh Abdi, on the biology of IL-12p40 in the immune system. At the same time we are interested in how distinct tissues in the body influence the magnitude and type of immune response that is mounted.
How we do it:Our laboratory uses a variety of techniques and approaches to tease apart how T cells and Dendritic cells work in vivo. We follow the behavior of these cells, by isolating them from mice for immediate flow cytometry (FACS) or cell culture. We use transgenic and knockout mouse models – as well as retroviral transduction of shRNA and CRISPRs - to evaluate many hypothesis. Overall the lab uses a wide range of molecular, biochemical, cellular and in vivo techniques. We also model diseases in mice caused by Leishmania, Toxoplasma, Plasmodium, Tumors and Autoimmunity.
Choose the titles on the side menu, to read more about our individual projects.