Detecting Germ Fighters in Plain Sight

When we think of our body's first line of defense against viruses, bacteria and other pathogens, we might envision T-cells and B-cells coursing through the bloodstream like soldiers on patrol. But what if this first line weren't these mobile warriors, but rather a group of immune cells standing at the ready, much closer to the front line? These cells exist, and their mechanics and makeup are being studied by a team of scientists led by Thomas Kupper, MD, BWH Department of Dermatology chairman, and Rachael Clark, MD, PhD, BWH assistant professor of dermatology.  

Kupper and Clark are recipients of one of 17 Transformative Research Awards awarded by the National Institutes of Health's (NIH) Common Fund in 2011. According to the NIH, "these awards are intended to support research that has the potential to transform the way we think about science, so the recipients represent an elite few with truly bold ideas with the potential to overturn scientific dogma and have a broad impact in medicine." With the $6 million grant, Kupper and Clark will study how certain T-cells play a role in initial immune response against infections and some cancers in the skin, lung, and gastrointestinal (GI) tract. They will also investigate how these cells can help create better vaccines.

‘Clear and Hold' Strategy

There are two main categories of T-cells: naive T-cells and memory T-cells. Both are made in the thymus gland and circulate in the bloodstream. While naive T-cells have never been exposed to a pathogen, memory T-cells have seen the "enemy" and have increased their numbers. When a virus enters the body, T-cells with receptors specific for that virus attack and kill cells infected by it. These T-cells log this experience into their memory, so when the same virus attacks in the future, these "memory" T-cells can immediately recall and respond.  

For some time, the accepted paradigm about immunity was that memory T-cells circulated in the bloodstream waiting for a pathogen to invade through tissue. Once this occurred, such as a virus entering through the skin, the cells would rush out of the bloodstream, enter the skin tissues, eliminate the virus, and then return to the bloodstream.

However, Kupper and Clark turned this long-accepted notion on its head when they discovered that a large component of these memory T-cells never returned to the bloodstream after attacking the virus. Instead they hunkered down in the tissue, waiting to encounter the next challenge--days, months and even years later.  

This immune response concept can be compared to a war scenario, with the battle between pathogens and self-tissue being fought in different ways. A failed strategy in war would play out as follows: Troops (T-cells) would come into a village (self-tissue) held by insurgents (pathogens), get rid of the insurgents, return the village to its inhabitants and then leave. But within days to months, the insurgents could come back with impunity and take over the village as if they had never left. This would require an expensive remobilization of troops from the bloodstream to get to the village and fight the same fight over again. This is an inefficient way to run an immune system, and a failed strategy in wartime.  

Thomas Kupper, MD

 A strategy that works would be that after troops clear a village of insurgents, they keep a presence by remaining in the village. Later, the insurgents see that the troops are there and as a result will not try to retake the village. If they do, they are quickly repulsed. In wartime, this is called a "clear and hold" strategy.

Incredibly, this is how Kupper and Clark think memory T-cell immune responses in tissues work. If all the immune system did was come into a tissue, fight an infection and then leave, there would be nothing to prevent that tissue from getting infected again.

"Now we know that immune cells come in, get rid of infection, and then leave some of the memory T-cells behind," said Kupper. "The next time an infectious pathogen tries to invade, it is dealt with immediately on site and cleared away."

In 2006, Clark and colleagues reported that normal human skin contains 20 billion memory T-cells, more than twice the number in blood. Kupper and Clark named these memory T-cells that stayed behind in skin tissue resident memory T-cells, while those that returned to the bloodstream were called central memory T-cells. Aside from skin, tissue resident memory T-cells have been found in lung, GI, oral and reproductive mucosal tissues.

"The old prevailing dogma in immunology is that most T-cell memory is mediated by central memory T-cells," said Kupper. "That turns out to be less than true. For pathogens you have encountered before, it's the memory T-cells resident in the peripheral tissues that protect you from future infections. Central memory T-cells are a wonderful source of reserves, but it is the tissue resident memory T-cells that do the hard work of protecting us. They really do seem to be our first line of defense."

Skin Deep: A Novel Approach to Vaccines

The discovery of immune cells in skin and other tissues has put a new spin on how scientists approach vaccine development. With the NIH award, Kupper and Clark will expand the work they have done in mice and humans by studying the unique populations of tissue resident memory T-cells in different human tissues. They will also explore the possibilities of making better vaccines to prevent many infections, diseases and cancer, based upon new ideas about how to generate these cells.

Traditionally, vaccines are designed to help the body produce circulating antibodies, which are made by B-cells. The antibodies then travel throughout the bloodstream, and then to tissues where they bind and inactivate the invading pathogen. Kupper and Clark surmise that if vaccines could be designed that would generate large populations of tissue resident T-cells in the relevant tissue, better vaccines could be developed.  Populations of lung resident T-cells might be a good solution for influenza, while memory T-cells resident in the GI tract and reproductive mucosa might protect against HIV better than circulating antibodies. It appears that special kinds of vaccination through skin are the best ways of generating tissue resident memory T-cells in tissue, whether skin, lung or the GI tract. 

"We feel very strongly that the best way to make a vaccine is to generate tissue resident memory T-cells that live in tissues," said Kupper. "This way, as soon as the virus crosses the epithelial surface it can be attacked and eliminated. We do not have to rely upon an antibody response."  This strategy closely mimics the natural behavior of the immune system.