Beyond antibodies: T-cells and long term immunity

Antibody levels and T-cells in the news

Worryingly, the percentage of people found to have antibodies to SARS-CoV-2 in countries that experienced early waves of infections is much lower than what we would need for ‘herd immunity’, and antibody levels drop in the weeks to months after recovery (see this blog post for a quick overview of the data).  Many people read headlines about numbers like this and assume that after antibody levels drop, we lose our immunity to SARS-CoV-2.  But an immune response never relies on a single ‘trick’. A central player in activating and coordinating immune responses is a type of cell called T-cells. These cells play a critical role both in how our bodies recognize and remove viral-infected cells and how we generate antibodies to directly target viral or bacterial pathogens.

T-cells are very much in the news in the past few weeks. A BBC article published on July 20th reported on findings of SARS-CoV-2 immunity in people who had no detectable levels of anti-coronavirus antibodies.  In fact, roughly half of the blood samples tested that were taken more than a year before current coronavirus pandemic contained T-cells that could recognize SARS-CoV-2.  A number of other recent posts and publications also discuss the role of T-cells in response to SARS-CoV-2 infection (see this recent NIH Director’s blog post, a blog post for Science Magazine, and article published in The Atlantic). 

While these are all interesting and informative posts, I don’t think they draw a clear picture of how the key moving parts of the immune system work together: how antibodies are made, how the body fights viral infections, the role of T-cells in both, and how all of this relates to immune memory.  My goal of today’s post is to hopefully lay out the pieces more clearly, ending with a discussion of how we can have long term immunity to a pathogen even after we no longer have antibodies to that pathogen in our blood.  For more about antibodies and antibody production, please read my earlier post on the topic before going on to read this post.

Antibodies, killer T-cells and helper T-cells

Our bodies respond to infections with a complicated series of interactions between different immune cells which ultimately allow the body to choose the best way to handle the challenge.  Antibodies, secreted proteins which can attach to the surfaces of pathogens, target infections when pathogens are between cells but have no effect on those already inside our cells.  Different forms of antibodies alert the body to different types of pathogens.  IgG antibodies are made in response to viral and bacterial pathogens; they steer the body toward an immune response that hunts down and destroys pathogens using immune cells like macrophages.  IgE antibodies are generated in response to parasites; they steer the body into an immune response that expels the parasite by triggering irritation (itching), the release of fluids (mucus, tears), and muscle contractions (sneezing, coughing, gut cramping).  In the absence of parasites, IgE based immune responses are sometimes triggered by pollen, molds, and some foods… basically what we call ‘allergy’ is a misdirected immune response whose intent is to eject a parasite from our skin, respiratory tract, or gut.

When a pathogen enters our own cells, we can think of it as an intracellular (“within cell”) parasite.  Antibodies can’t move across our cell membranes, so pathogens inside our cells are protected from any immune response those antibodies would trigger. To tackle these internal pathogens, the immune system relies on a type of cell called a T-cell, specifically a type of T-cell called a killer T-cells (aka CD8+ T-cells or CTLs, for “cytotoxic lymphocytes).  Killer T-cell must be able to ‘see’ that a cell is infected to ensure that they kill infected and not healthy cells.  Rather like a quality control protocol for a factory (like this one), every cell in our body uses a type of protein (called “HLA”, and also, confusingly, “MHC”) to randomly grab samples of the different proteins present inside it which it then displays on the cell surface. 

Killer T-cells are “quality assessment’ cells, checking the samples to see if the proteins on display are normal, foreign or defective.  They do this using a type of protein attached to their surface called a T-cell receptor (TCR). The same way each new B-cell our body ever produces makes a unique, randomly generated antibody that binds a different target from all other antibodies (for more, see my previous post), each new T-cell we ever produce makes a unique, randomly generated T-cell receptor with its own particular shape.  This shape is used like a ‘search image’ to check all the different pieces of proteins our cells display.  If a displayed protein has the right shape, it will fit into the TCR of one of our many, many T-cells.  When a T-cell’s receptor binds a target in this way, the T-cell begins to activate.  Exactly what it does once it is activated depends on what type of T-cell it is.  Activated killer T-cells recognize and destroy cells showing off viral or bacterial proteins as well as cells showing off defective proteins, like cancer cells.  ‘Helper’ T-cells (also called CD4+ cells), when activated, ‘help’ other parts of the immune system to become active.

How does a T-cell ‘know’ if a protein is normal or defective/foreign?  All newly made T-cells are tested (in the thymus) to make sure they can’t bind the proteins shown off by normal healthy cells.  If an immature T-cell does bind one of these normal proteins, it is destroyed before it can be released into the body.  Any protein a surviving T-cell can bind, therefore, must therefore be foreign or defective. T-cells that don’t bind ‘self’ proteins are allowed into the blood, where they circulate in and out of lymph nodes checking for proteins they can recognize. 

Having a type of cell that can destroy our own cells is dangerous, so the initial activation of killer T-cells especially is tightly controlled.  Even if a killer T-cell can bind a displayed protein on an infected cell, it can’t activated until it is ‘licensed to kill’ (yes, that is a James Bond reference!).  The key player in this control are the “helper” T-cells. For a killer T-cell to become active, it must bind a displayed protein on a cell at the same time a helper T-cell is also binding a separate protein displayed on the same cell. If both types of T-cells simultaneously recognize something ‘wrong’ with the target, signals released from the helper T-cell (called cytokines) push the killer T-cell to become fully activated (“licensed”). 

Helper T-cells also help in the activation of antibody-producing B-cells.  Because antibodies circulating through our blood and tissues could possibly bind to surfaces of our own bodies and trigger damaging immune response (as they do in autoimmune diseases like lupus), their production must be tightly controlled so that they are only produced in response to an infection. In order for a B-cell to activate and begin producing antibodies, it must first attach to whatever its antibody can bind and then draw that target into itself. The target is then broken down inside the B-cell, releasing all the proteins it contained. Like in the quality control process of all our cells, any proteins present in a B-cell are sampled and shown off on the B-cell’s surface.  If an active helper T-cell recognizes a protein a B-cell is displaying as being foreign/defective, it sends that B-cell signals (again, cytokines) that will push the B-cell into antibody production. 

You might be wondering at this point how helper T-cells become active in the first place.  To explain that would require describing the innate immune response….  Which I may do in a separate post, but would take us down a rabbit hole here, and I’m pretty sure I would exhaust your attention (if I haven’t done so already!).  For now, the key thing to see is that helper T-cells are major players in both antibody production and killer T-cell activation.

Immune memory cells, B and T

When our bodies respond to an infection, any cell that becomes activated, B-cells, killer T-cells, and helper T-cells, divides to make an army of identical or nearly-identical daughter cells.  This rapidly expands the immune system’s ability to respond specifically to the target that triggered the activation of that subset of cells.  Most of those daughter cells become ‘effector cells’ and go off to fight the good fight.  Some of the daughter cells actually become quiet, dialing down their activity until they look almost like any other inactive B-cell or T-cell.  These are our ‘memory’ cells, cells that are the products of an immune response that the body keeps in reserve against the possibility of a reinfection by the same pathogen.  Unlike brand new naïve B- and T-cells, when a memory cells meets a pathogen for the second time, it activates quickly and aggressively, which results in a bigger, faster, stronger immune response (see this article for more info).  We all have memory B-cells, memory killer T-cells, and memory helper T-cells circulating in our blood that were made in response to infections, and vaccines, we’ve encountered in the past.  Memory cells can last longer than ‘regular’ B and T cells.  Exactly ow long they last is still an open question, but it seems to depend on the nature and intensity of that first immune response and how often the memory cells ‘meet’ that first pathogen again. 

What do we know about the formation of memory cells that can recognize SARS-CoV-2?First and most importantly, we know that people who recover from SARS-CoV-2 infection have solid memory T-cell populations even after they no longer have coronavirus antibodies in their blood, though the exact number and nature of those memory cells may depend on the severity of infection and the person’s age.  This is great news for those who have recovered from infection, and also hopeful news for vaccine development.  Exactly how long this memory endures is not clear yet, but generally immune memory lasts for years or even decades, depending on the pathogen/vaccine that first triggered the immune response.

A second surprising finding is that a fairly sizable fraction of people who have never been exposed to the SARS-CoV-2 virus have memory T-cells that can at least partially recognize the virus.  In a key study, researchers took blood samples donated between 2015 and 2018 (in the U.S.) and isolated T-cells from each sample. They then exposed those T-cells to SARS-CoV-2 proteins under conditions that allow memory T-cells to activate but not naïve (never-before-activated) T-cells. Surprisingly, about half of the samples had memory T-cells that can respond to SARS-CoV-2.  Similar results were found in other studies (see study 1, study 2). Were the people with ‘good T-cells’ exposed to SARS-CoV-2 in the past?  No – we know this virus emerged sometime in 2019 and wasn’t in the U.S. in 2018 or earlier.  But SARS-CoV-2 shares similarities with coronaviruses that have circulated in human populations for decades or more.  It seems that one or more of these other coronaviruses can act a bit like a vaccine, allowing the body to have some ability to respond to this new virus, though maybe not as effectively as it would to the virus that triggered the original immune response.

What does this mean for us, right now?

Researchers are working at breakneck speeds to understand SARS-CoV-2, but good science takes time, care, repetition and discussion.  This virus can move through our population much faster than scientists can discover critical information about it.  Unless we are researchers, doctors or epidemiologists, we can’t make that work go faster.  What we can do is buy the researchers more time to complete their work by slowing the spread of this virus with good public health policies, and compliance with those policies.  Patience is difficult.  Waiting is difficult.  Staying home, wearing masks, and limiting contact are all difficult.  But unlike so many aspects of this pandemic, we have control over our own actions.  By adding each of our small pieces together, we can build a wall against the spread of this virus.  Yes, the wall will be imperfect and won’t make the virus disappear, but it will give us and our scientists the time it takes to do good science, to learn information critical to halting this pandemic in its tracks.

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