When antibody levels go down, T-cells have your back.

More than any other facet of Covid-19, the question of immunity has been a stressful source of good news/bad news whiplash.

Good news: Scientists discovered early on that most people who have been infected with SARS-CoV-2 (the official name for the novel coronavirus) create virus-specific antibodies — special proteins produced by immune cells that help fight off the coronavirus and provide immunity against future infections. This finding helped guide the dozens of vaccines currently under development.

Bad news: Those antibodies may hang around for only a couple months, a phenomenon called waning immunity. There have been anecdotal accounts of a few people potentially contracting the virus a second time, and a new preprint paper — which has not yet been peer reviewed — showed that in some recovered patients, antibody levels declined to undetectable levels after three months. These reports have caused some people to speculate that a vaccine will be largely ineffective and that we may never develop herd immunity to the virus.

Before you start to doom spiral, though, let’s turn back to good news: Antibodies aren’t the only tools the immune system has to fight repeat invaders. Several recent studies have shown that in addition to antibodies, people also develop virus-specific T cells. These immune cells are an important component of long-term immunity, and in some cases they’re detectable in the body many years after antibodies dissipate. But because nothing is simple with SARS-CoV-2, the T cells produced in response to the coronavirus are a little unusual.

B cells and T cells work as a team

The immune system has two waves in its defense against an invader: the initial innate response, which looks the same for pretty much any attacker, and the slower adaptive response, which takes about a week to develop but is tailored to the current assailant. The adaptive response also serves as a type of immunological memory, so that if the same virus tries to reinfect a person, their immune system can kick into gear and immediately mount a virus-specific defense. It’s this second phase that scientists are especially interested in right now, because it’s also the one that’s activated by vaccines.

There are two main cell types involved in adaptive immunity that work as a team, B cells and T cells, both of which are white blood cells — technically called lymphocytes — that primarily live in the lymph nodes. B cells make antibodies, those coveted proteins that latch onto the virus and either disarm it or block it from entering the body’s cells. But in order to learn what the virus looks like and what kinds and shapes of antibodies to make, B cells need T cells.

Even if “antibody levels are quite low in coronavirus infection, having T cells around to get them up quickly will give you quite a bit of protection.”

“To make really good quality B cells and get good antibodies, you need T cell help,” says Richard Locksley, MD, a professor of medicine at the University of California, San Francisco. For example, he says, “When you get a vaccine, like a flu vaccine or a tetanus toxin or whatever, the T cell help is what makes you get the good antibodies by the B cells.”

There are several different flavors of T cells that play a role in the immune system, but the two variations that are especially important when it comes to immunity are referred to as memory T cells, because they remember the virus in case it comes back. The first memory T cells, known as “helper” T cells, educate the B cells about what the antibodies should look like to combat the current invader. They also provide the B cells with growth factors and general support to produce as many antibodies as possible.

The other kind of memory T cells are called “killer” T cells. These T cells also learn what the current viral threat looks like, and they go off to find infected cells and destroy them so the virus can’t spread further inside the body. One expert called them “the special forces” of the immune system.

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When antibody levels go down, T cells have your back

Several studies have shown that people who were infected with the novel coronavirus create memory T cells that react specifically to SARS-CoV-2. In one paper published in June, 100% of people who had recovered from mild Covid-19 infections developed virus-specific helper T cells, and 70% developed killer T cells. A follow-up study by the same scientists similarly found that, in people who were hospitalized with severe Covid-19 infections, 100% produced helper T cells and 80% produced killer T cells. Two other groups in Germany and Sweden have released preprint papers showing similar results.

“The good news is, despite all the worries at the time that there was no immunity whatsoever, we did find immunity in all the factors that we analyzed,” says Alba Grifoni, PhD, a scientist at the La Jolla Institute who worked on both of the published studies. “One month after the infection, we were able to detect a good immune response both for the B and T cell sides.”

The discovery of virus-specific memory T cells is good news for several reasons. First, those T cells boost the immune response and help guarantee that B cells create high-quality antibodies. Potentially even more important is the fact that the memory T cells can remain in a reservoir in the body for a long time, in some cases for decades. This fact is especially critical in light of the possibility that SARS-CoV-2 antibodies might decline rather quickly. Memory T cells can remind the B cells which antibodies to make, replenishing the pool on command.

“But what we think happens is almost all of those patients will have T cell memory, and the T cells seem to be quite durable.”

“The advantage of having really good T cells is even if the antibody levels have gone down, every time you get exposed again, the T cells will clone up and provide help really quickly, and those antibodies will be expanded again,” Locksley says. Even if “antibody levels are quite low in coronavirus infection, having T cells around to get them up quickly will give you quite a bit of protection.”

Based on what scientists know about SARS and MERS, coronaviruses related to the current infection, there was speculation that SARS-CoV-2 antibodies would provide immunity for several years. Since the new coronavirus has been circulating for only six months, it’s too soon to know how long the antibodies will last, but the latest research suggests that the timeline might be months rather than years, especially in people who had mild or asymptomatic infections.

“There’s some information now emerging that antibodies may decline over time,” says John Wherry, PhD, director of the Institute for Immunology at the University of Pennsylvania. “That concerns some people, suggesting that our antibody memory, our protective immunity, may wane over time. Jury’s still out on that. But what we think happens is almost all of those patients will have T cell memory, and the T cells seem to be quite durable.”

Scientists don’t yet know how long SARS-CoV-2 T cells will last, but one recent study published in the journal Nature found that people who were exposed to the original SARS virus in 2003 still had T cells that responded to the virus in 2020, 17 years later.

Some people’s immune systems might be handicapped by the virus, while others may have a running start

Of course, it can never just be easy with this virus. While people do produce T cells in response to SARS-CoV-2, evidence has emerged that the cells are delayed, suppressed, and out of balance — a phenomenon known as lymphopenia, meaning a deficiency of lymphocytes. Disrupting the immune system isn’t unique to the coronavirus, virtually all viruses do it to some extent to help them thwart the immune response. But in SARS-CoV-2, the lymphopenia is more severe and appears to target the killer T cells.

“When you see this lymphopenia, the loss of lymphocytes, in other infections, often it’s B cells and T cells and the other minor [cell] populations. In SARS-CoV-2, it seems to be preferentially impacting the [killer] T cells,” says Wherry, who released a preprint paper on the finding. “We don’t really know why. That occurs in some other very severe infections — it can occur in Ebola, it may occur in some others — but it’s a little bit unusual. It’s also unusual for the lymphopenia to be lasting a long time. In other infections, it tends to be very transient, only lasting for maybe a few days.”

“I think this is working like lots of viruses work, and it’s going to hit these pathways we know about. And maybe tucked in there will be some new surprise that will guide the way to a better way to treat not only this virus, but other viruses.”

Lymphopenia is more pronounced in people with severe Covid-19 infections, although scientists don’t know if it is the cause or the result of the prolonged, exhausting war the immune system wages against the virus. One possibility is that without the anticipated T cell response, the initial innate immune defense goes into overdrive, resulting in the so-called cytokine storm, where inflammatory immune proteins cause irreparable damage to the body’s tissues. The adaptive immune system does rebound eventually, though, and people who recover from the virus produce adequate numbers of B cells and T cells to fight off the infection.

Another question mark when it comes to T cells is the discovery by Grifoni and others that up to 50% of people have memory T cells that respond to SARS-CoV-2, even if they’ve never had the virus. The leading theory is that exposure to other similar coronaviruses, like the ones that cause the common cold, prompted people to produce T cells that also respond to the new strain. This discovery could potentially explain why some people have very mild or asymptomatic infections — perhaps their immune systems have a running start to mount a response and quickly produce antibodies to the novel coronavirus.

Grifoni says these cases are important to keep in mind for vaccine development, because a higher baseline level of memory T cells could influence how a person’s immune system responds to the vaccine, potentially speeding up their production of antibodies and enhancing their protection against the virus. “If you have a T cell response before the vaccine, and you don’t measure that and just look at the response after the vaccination, you would not know whether [the vaccine actually worked or] you got lucky,” she says. “You need to look at what was the [T cell] response before.”

While there are still a lot of unanswered questions when it comes to the novel coronavirus, the good news is that scientists do know a lot about the immune system, and they’re working at record speed to figure out how it responds to this particular virus.

“I don’t think all of a sudden something is going to work in some bizarre way we’ve never seen before. I think this is working like lots of viruses work, and it’s going to hit these pathways we know about,” Locksley says. “And maybe tucked in there will be some new surprise that will guide the way to a better way to treat not only this virus, but other viruses.”