Circadian Clock Controls Immune Response…What?

Jessica Ebert
by Jessica Ebert

I live for being wowed. Who doesn’t really? Who doesn’t get a kick out of finding something special in unexpected places or seemingly unexceptional people? It could be something simple like a single line in a song at the end of a really good movie. A single line that forces you to Google that combination of words to reveal the songwriter and then YouTube the songwriter to unveil all the pixelated videos with the muffled, strangely distant-sounding lyrics (except, of course, for the inevitable fan from the audience, singing off key, who is always, always the loudest, clearest voice in the video).

Or it could be something a bit more scientific like…a recently published paper in the journal, Immunity.

Before I go any further, you should know that I work really hard to avoid the subject of immunology. I run from phrases like “innate immune response” and “action of complement.” I cower and then scramble to hide from the mountains of acronyms, which form a language unto themselves: CDthis cell and CDthat cell, and ILthis and ILthat, and pathogen-associated molecular patterns (PAMPs) and their corresponding pattern-recognition receptors (PRRs), and on…and on…and on.

But I needed a paper, a fresh, new paper, for my writing students to use to practice their critical reading and summarizing skills. I usually don’t pick something quite as challenging as an immunology paper, but people were talking about it. It was getting media attention. Anahad O’Connor (reporter for the New York Times) had blogged about it. It must be special.

And although I’m not an expert, I think it is, special that is, something with a bit of the wow about it. Here’s why:

Once upon a time there was a receptor. It was a mighty receptor expressed in immune cells like macrophages. The receptor is called Toll-like receptor 9 or TLR9 for short (one of those pesky acronyms, of course!). TLR9 works by recognizing the DNA of foreign bacteria or viruses and then triggering both the innate and adaptive immune responses.

The new news, as discovered and reported by a team of scientists from Yale University School of Medicine and Howard Hughes Medical Institute is this: the expression of TLR9 is controlled by the circadian clock. What?

Circadian rhythms are predictable oscillations in biological processes that are driven by environmental cues like light versus darkness. In mice spleen cells and macrophages (as well as a couple other immune cells), TLR9 expression shows a daily peak and nadir. When mice are vaccinated at the peak of TLR9 expression, lymphocyte cultures show an increased adaptive immune response compared to mice vaccinated at the nadir of TLR9 expression.

In addition, when mice are given cecal ligation and puncture surgeries (i.e. when they are essentially challenged with bacterial sepsis) at the peak of TLR9 expression, the mice present with a more severe sepsis phenotype than those mice treated when TLR9 expression is at its lowest point.

These results have all sorts of implications for treatment and patient practice. For instance, maybe part of a vaccination plan should take into consideration the time of day the vaccine is administered…maybe an intensive-care-unit patient should be allowed to sleep through the night instead of being woken up regularly for various checkups…maybe part of any treatment protocol should encourage the maintenance of normal circadian patterns.

But I think the evolutionary implications of this study are even more fascinating. Have certain immune responses evolved to be strongest at the times of day when we are most likely to encounter a pathogen? And conversely, have pathogens and/or their vectors, such as mosquitoes, changed their behaviors or activities over time to attack when the expression of certain human immune response molecules is lowest or least effective?

I always thought I had a clear understanding of the “arms” race between microbes and humans—we observe pathogens emerging and/or evolving and we find new ways to control them. But now, I’m starting to wonder if there’s also this other kind of race underway that we aren’t really aware of.

Maybe this Immunity paper is just another in a long line of papers that link circadian rhythms to an immune response. I don’t know enough about the field to know if that’s the case, but I don’t really care. This paper was special to me, because it made me think. It wowed me.

If you’re interested, here’s the citation for the paper: Silver, A.C., Arjona, A., Walker, W.E., and Fikrig, E. (2012). The circadian clock controls toll-like receptor 9-mediated innate and adaptive immunity. Immunity 36, 251-261.