FRIDAY! September 7th, 2012
Central Park East - 6:45am

Good morning!  Ready for installment #2 of "What is it you do all day?"

Well I present to you, lesson #2:  What does any of this have to do with Jen's research?

Well if you recall, we talked about basic cell biology in Part I.  When T cells in the lymph node sense that there is a pathogen present, they start making their signal to divide - Interleukin 2 - replicate, and then help the B cells make antibodies, which will contribute to getting rid of or "clearing" the pathogen. 

How do the surrounding T cells in the lymph node sense that there is Interleukin 2 around?  They have a specialized receptor on their cell surface that detects specifically Interleukin 2. 

Well, the next step is something that is often taken for granted in high school or even college level cell biology classes.  The canonical teaching ignores the fact that Interleukin 2 isn't magical and can't change gene expression just by landing on the surface of the cell.  If you were in a room with no windows, you wouldn't know it was snowing just by snow hitting the roof.  You would have to wait for someone to come inside and tell you that it was snowing! The same goes for our T cell.  There has to be a second messenger at the inside of the cell membrane that goes and tells the nucleus how to change it's gene expression once Interleukin 2 is sensed. 

That molecule is called "STAT5."  The name isn't important - what is important is that STAT5 hangs around on the inside of the interleukin 2 receptor that sits inside the cell.  By itself, STAT5 can't enter the nucleus.  However, once Interleukin 2 receptor senses Interleukin 2, STAT5 is phosphorylated, which permits it to enter the nucleus and change gene expression.  Phosphorylation is a common method of signalling in a cell.  Basically it means that a big negative charge was tacked onto the molecule, which changes how it behaves biochemically.  If I lose you, it's not a big deal - what you need to know is that if STAT5 is phosphorylated (we call it pSTAT5), then the cell is "seeing" Interleukin 2.  If not, then there's no Interleukin 2 around. 

There's one more thing I should mention.  We can measure the amount of pSTAT5 in the cell.  We can also measure the amount of Interleukin 2 receptor on the surface of the cell.  For technical reasons, it's a little more difficult for us to measure the amount of Interleukin 2 floating around in the lymph node. 

Now, what exactly does that Interleukin 2 and pSTAT5 tell the DNA in the nucleus to do?

Well, here's where things get interesting.  In biology and in life nothing is black and white and in the case of T cells, nothing is "on" or "off."  We don't run our bodies like molecular on/off switches because it's too easy for something to go wrong.  Rather, there is always a balance of on and off switches happening at the same time.  The signal that predominates is the signal that is sent. 

In your lymph node, there are a bunch of T cells floating around that don't actually contribute to fighting off pathogens.  These T cells are called "Regulatory T cells."  A man that works down the hall from me named Sasha Rudensky was one of the first people to discover regulatory T cells.  Regulatory T cells have a constant low number of Interleukin 2 receptors on their cell surface. 

Why do you think that is?


Are you thinking?........


In this case, the Interleukin 2 receptors on the surface of the regulatory T cells act as molecular sponges.  Interleukin 2 is an activating signal.  There is constant low level stimulation causing production of Interleukin 2 in your lymph nodes, but not always because there's an actual pathogenic threat.  It's because your body isn't perfect and sometimes can't tell whether parts of you are foreign or you.  If there is only a little big of Interleukin 2 around, the Regulatory T cells will soak it all up and prevent any helper T cells (T cells that help B cells make antibodies) from seeing it.  This is SO important because if your T cells just react to any old Interleukin 2 they see, then you'll be in a full blown autoimmune disease state.  In experiments where they depleted the regulatory T cells out of mice, the mice developed SEVERE multi-organ failure because their own T cells attacked every organ system they had. 

I didn't draw it in the above picture, but these regulatory T cells sensing low levels of Interleukin 2 will be phosphorylating STAT5 and we will be able to measure that.  The measurement of pSTAT5 will be low, though, because there is only a little big of Interleukin 2 floating around and interacting with Interleukin 2 receptors. 

However, if there is a legitimate threat, much higher amounts of Interleukin 2 will be made and it will saturate all available receptors for the regulatory T cell.  This will make some available for the activating T cells, which have fewer Interleukin 2 receptors in their resting state. 

Once the activating T cell finally sees Interleukin 2, it BLASTS, meaning it does 2 things:  First, it divides and makes more of itself.  Second, it makes more Interleukin 2 receptor.  (Remember cell division and manufacturing of Interleukin 2 receptor are all as a result of gene expression changes that happen in response to the signal from pSTAT5).  This tips the immune "ON" switch even further because now the activating T cells are both more frequent and have more Interleukin 2 receptors.  They can now go help B cells make antibody and fight off the threat. 

Now what do you think will happen when we measure the amount of Interleukin 2 receptor and pSTAT5 in the cells?  The measurement of both will be MUCH higher!

We can actually represent what happens using a curve:

That's all I'll tell you about today.  If you're confused about the curve, that's ok - I'll explain it more on Monday during Part III - "Ok I get it, but why would you ever want to know this?"