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Immune response from start to finish: Part 3

October 5, 2010

[I’ve been hooked on the immune system since I was a kid and my dad showed me electron micrographs of macrophages eating bacteria in Scientific American. Now that I’m in graduate school studying immunology, and macrophages in particular, my dad asked if I could give a play-by-play of an immune response. Here you go Dad:]

Part 3: Immune memory

Towards the end of the 18th century, Edward Jenner did an experiment. It had long been known that people who had been infected with smallpox, if they managed to survive (no easy feat), would be resistant to further infection. People would even give small inocula of smallpox to healthy people in an effort to prevent a more serious infection (though this wasn’t very controlled and would often lead to serious illness and death). But there was also anecdotal evidence that milkmaids, who were often afflicted by the much milder disease cowpox, were also resistant to smallpox. So, Jenner devised the hypothesis that cowpox was close enough to smallpox that it would teach the body how to fight both. And he tested it – by injecting James Fipps (the 8 year old son of his gardener) with puss from a cowpox sore. Unsurprisingly, the kid got cowpox, and when the infection cleared, Jenner then injected the same boy (why this kid didn’t run screaming, I will never understand) with puss from someone with smallpox. Magically, the boy did not get small-pox. Thus, Jenner is credited with devising the first vaccine. In fact, the name vaccine comes from “vacca,” the latin word for cow.

Even with all the “controversy” about vaccines, the fact is that they work. One of the benefits of being a chordate is that we have an adaptive immune system, and that branch of the immune system remembers. In the last part, I talked about the T-cells and B-cells of the adaptive immune system. These cells have special, randomized receptors, and each individual cell recognizes something unique. During the course of your life, you’ll make hundreds of billions of different T cell and B-cell receptors, and most of them will never be used. But during an infection, some of the T and B cells will respond, and during that response, they will replicate. Most of the daughter cells will become effectors, and do all the disease-fighting things I talked about before, but a small percentage will become memory cells.

At some point, all of those effector cells have to die off – if they didn’t, after a couple times getting a cold, you’d end up being a giant lymph node. But memory cells know they’re important, and can survive for years or even decades. Because they were activated in the presence of an infection, they can be sure that their receptor recognized something foreign that is potentially dangerous. And if that something rears its head again, the memory cell can rapidly proliferate and produce new effector cells, all without waiting for a dendritic cell to say that it’s ok. In addition, memory B-cells can continue to secrete antibodies, which patrol your bloodstream, just waiting to encounter that pathogen once again.

This last bit is what makes vaccines possible. When Jenner infected James with cowpox, the boy’s immune system responded. Dendritic cells from his skin grabbed bits of the cowpox virus and brought them to lymph nodes to show to T and B cells. Some of those T and B cells had receptors that could recognize those bits, and they expanded and differentiated to run off and battle the infection. Meanwhile, some of them held back and turned into memory cells, and the memory B cells in particular continued to churn out cowpox-specific antibodies. Weeks later, when Jenner inoculated him with smallpox, there were already millions of cowpox antibodies flying around his bloodstream. Since smallpox is closely related to cowpox, many of those antibodies could recognize the virus particles and bind to them, preventing them from infecting any of the boy’s cells. If any viruses slipped by and actually infected a cell, the memory T cells would be alerted and blast the infected cell before it could make many new viruses. And if that cell did manage to make new viruses, those new viruses would also have to get by the antibody wall.

That’s the immune response in a nutshell. To recap: Innate immunity tags and bags most things that get past your barriers, then the adaptive immune response picks up the stuff that gets through, and remembers what infected you so that it can respond better the next time. That’s how I learned it in my undergraduate immunology class. That’s how it’s being taught to the undergrads I’m teaching now. Simple right?

Well, not so fast. If it’s that simple, why don’t we have vaccines against the legions of bacterial infections that debilitate or kill people every year (not to mention HIV), and why do we need a new flu vaccine every year? Why are over 90% of adults chronically infected with various strains of herpes virus? And why are there billions of dollars to be made in drugs that slow the immune system down? I’ll talk about some of the nuance and the complications of our sophisticated immune system next. Stay tuned.

Immune response from start to finish series
Part 1: Invasion and detection: Innate immunity
Part 2: T-cells, B-cells and adaptive immunity
Part 3: Immune Memory (current)

9 Comments leave one →
  1. James permalink
    October 5, 2010 5:10 am

    This series is really well written. I was wondering if you would have any problem with me circulating it amongst my students? I’m a bacteriologist so sometimes the immune system comes across as a little foreign to me, although I do my best.

    • Kevin permalink*
      October 5, 2010 1:55 pm

      I’m glad you like it, and I’d be delighted if you showed it to your students. Also, if they have any questions, they’re more than welcome to ask in the comments.

  2. October 15, 2010 12:53 pm

    Fantastic series, thanks. I’m not a scientist but am totally fascinated by immunology and particularly immunological memory, it’s amazing to see the insights that are being gained now with gene expression and imaging studies. There’s been a couple of cool papers recently about how memory CD4 T cells can recruit innate immune responses, a kind of cooperation between adaptive and innate immunity that I don’t think was well appreciated before:

    Also in terms of HIV, this paper from John Zaunders found that HIV DNA is preferentially concentrated in developing memory CD4 T cells (identified on the basis of IL-7 receptor expression) during acute infection, which seems like a big clue as to why memory CD4, CD8 and B cell responses against HIV become functionally compromised and are not able to control the infection they way they typically do with viruses like EBV and CMV.

    • Kevin permalink*
      October 15, 2010 3:12 pm

      Kudos to you for not being a scientist and reading scientific papers. I AM a scientist and I have a lot of trouble staying on top of it.

      Cross-talk between innate and adaptive immune responses are legion. It’s been known for 50 years that IFNg secreted by T-cells can change the way macrophages behave. And the innate immune system is known to instruct the adaptive immune system based on cytokine secretion. I hadn’t seen that Nature Med paper you linked to, it’s pretty cool, and I’m sure it won’t be the last example of this.

      I’m not up to date with HIV research, but it certainly seems like that virus is exquisitely good at circumventing the immune system on multiple levels. There are a lot of people here at Harvard that study this “T-cell exhaustion” that seems to happen with many chronic infections, but especially with HIV.

  3. Dennis Bonham permalink
    October 17, 2010 9:03 pm

    I compliment you on writing this very interesting easy to read series. What Edward Jenner did is very unethical by today’s standards and he would have been sued and arrested if that happened today. If Jenner was so sure of his hypothesis, then he should have done this experiment on himself. So, good for him for devising the first vaccine but shame on him for using his gardener’s son for the experiment.

  4. Kwanmor permalink
    December 9, 2010 4:13 am

    I would like to know the fate of any memory cell once reactivated. Specifically, I would like to know if they give rise to effector cell as well as another memory cells with same quality or all will differentiate into just effector cells.
    Thank you very much for your informative writing.

    • Kevin permalink*
      December 10, 2010 10:38 am

      Thanks for reading (and check out our new site:

      The answer to your question is that when memory cells respond, they differentiate (we think) into lots more effector cells – that’s why we keep them around. But we definitely retain memory cells as well, often in increased numbers. In addition, memory B-cells can undergo further rounds of somatic hypermutation (where they mutate their receptor) and end up with even higher affinity antibodies.

  5. cindy permalink
    May 11, 2012 11:48 pm

    Hi Kevin, I’m in an undergraduate course ( actually my first microbiology class) and on our final the prof wants us to describe a disease from staphylococcus or malaria or maybe tb starting with inflammation and heavy emphasis on complement (including all the scientific names that accompany complement). Any suggestions? Feeling overwhelmed in California!


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