Natural Immunity to Sars Cov-2 due to T-Cell Cross-Reactivity

“A short excursion into the field of immunology.
What does immunity against coronaviruses depend on?The coronavirus binds via protein projections (so-called spikes) that recognise specific molecules (receptors) on our cell. This can be likened to virus hands grasping the handles of doors that then open to allow entry. After multiplication, viral progenies are released and can infect other cells.
Immunity against coronaviruses rests on two pillars: 1) antibodies, 2) specialised cells of our immune system, the so-called helper lymphocytes and killer lymphocytes. When a new virus enters the body and causes illness, the immune system responds by mobilising these arms of defence. Both are trained to specifically recognise the invading virus, and both are endowed with the gift of long-term memory. Upon re-invasion by the virus, they are recruited to the new battle sites, their prowess bolstered through their previous encounter with the sparring
partner. Many different antibodies are generated, each specifically recognising a tiny part of the virus. Note that only the antibodies that bind the “hands” of the virus are protective because they can stop the virus from gripping the handles of the door. Classical viral vaccines are designed to make our immune system
produce such antibodies. It is believed that an individual will thus become immune to the virus.
Three points require emphasis.

  1. If you are tested for SARS-CoV-2 antibodies and nothing is found this does not mean that you were not infected. Severe symptoms often correlate with high production of antibodies, mild symptoms only lead to
    low antibody levels and many asymptomatic infections probably occur without any antibody production.
  2. If antibodies are found this does not mean that you are immune. Current immunological tests cannot selectively detect protective antibodies directed against the “hands” of the virus. Other antibodies show up at the same time. Testing cannot give any reliable information on the “immune status” of an individual and, as will follow next, is essentially useless.
  3. The outcome of an encounter between “protective” antibodies and the virus is not “black or white”, not a “now or never”. Numbers are important. A wall of protecting antibodies may ward off a small attack –for instance when someone coughs at a distance. The attack intensifies as the person comes closer. The scales begin to tip. Some viruses may now overcome the barrier and make it into the cells. If the cough comes from close quarters, the battle becomes one-sided and ends in a quick victory for the virus.
    So even if vaccination is “successful”, meaning that production of protective antibodies has taken place, it does not guarantee immunity. To worsen matters, antibody production spontaneously wanes after just a few months. Protection, if any at all, is at best short-lived.
    The idea of a personal “Immune Status” document is scientifically unsound.
    What happens after the virus enters the cell? Experiments conducted on mice have examined this in detail for SARS-CoV, the original SARS virus and close relative of the present SARS-CoV-2. It was demonstrated that the second arm of the immune system comes into play. Lymphocytes arrive on the scene. A coordinated series of events takes place during which helper cells explode into action and activate their partners, the killer lymphocytes. These seek out the cells that contain the virus and kill them. The factory is destroyed – the fire is extinguished.
    Cough and fever go away.
    How can killer lymphocytes know which cells to attack? Put in simple words: imagine an infected cell to be a factory that produces and assembles the virus parts. Bits and pieces that are not assembled into the viruses become waste products that the cell removes in an ingenious way: it transports them out and puts them in front of the door. The patrolling killer cells see the trash and move in for the kill.
    This second arm of our immune system is seldom talked about, but it is probably actually all-important – much more so than the antibodies that represent a rather shaky first line of defence. Most importantly, waste products derived from different coronaviruses share similarities. Killer lymphocytes recognising the waste of one virus can therefore be expected to recognise at least some of the waste of others.
    Would this imply cross-immunity?
    Yes. Coronavirus mutations take place in very small steps. Protective antibodies and lymphocytes against type A will therefore also be quite effective against progeny Aa. If B comes to visit, you get another cold and cough, but then your immune status broadens to cover A, Aa, B and Bb. The scope of immunity expands with each new infection. And lymphocytes can remember.
    Who does not recall their child’s first year in kindergarten? Oh no, not again, here comes the umpteenth cold with runny nose, cough and fever. The child is ill all through the long winter! Luckily, it gets better the second year and the third will be weathered with maybe just one or two colds. By the time school starts,
    the operational base for combating the viruses has grown rock solid.
    So what does “Immunity against coronavirus” really mean?
    Does “immune” mean that we do not get infected at all?
    No. It means we don’t fall seriously ill.
    And not getting sick does not rest solely on prevention of infection by antibodies, but more on “putting out the fire”. When a new variant appears, many people may get infected but because the fires are quickly extinguished, they will not fall seriously ill. The relative few who fare worse do so because the balance between attack and defence is heavily in favour of the virus. But in the absence of pre-existing illness, the scales tip back again. The virus will be overcome. As a rule, it is only for people with pre-existing conditions that the virus may become the last straw that breaks the proverbial camel’s back. This is why coronavirus infections run a mild or even symptom-free course and why an epidemic with any “new” virus is never followed by a second, more serious, wave.
    Why do annual coronavirus epidemics end in summer? Well, just one speculation. Over 50% of the northern European population becomes vitamin D deficient in the dark winter months. Possibly, replenishment of vitamin D stores by sunshine and the shift of activities to outdoors are simple important reasons.
    What happens to the virus after an epidemic? It joins its relatives and circulates with them in the population. Infections continue to occur but most go unnoticed because of the vitalised immune system. Once in a while, someone will get his summer flu. But such is life.
    Can a similar pattern be expected with SARS-CoV-2?
    The authors believe that is exactly what we have witnessed. 85–90% of the SARS-CoV-2 positive individuals did not fall ill. Most probably, their lymphocytes extinguished the fires in time to limit viral production. Put very simply: the virus was a new variant and able to infect almost anyone. But immunity was already widespread due to the presence of lymphocytes that crossrecognised the virus.
    Does proof exist that lymphocytes from unexposed individuals cross-recognise SARS-CoV-2?
    Yes. In a recent German study, lymphocytes from 185 blood samples obtained between 2007 and 2019 were examined for cross-recognition of SARS-CoV-2. Positive results were found in no less than 70–80%, and this applied to both helper and killer lymphocytes.
    A US study with lymphocytes from 20 unexposed donors similarly reported the presence of lymphocytes that were cross-reactive with the new virus.
    In these and another Swedish study it was also found that even non-symptomatic or mild SARS-CoV-2 infections provoked strong T-cell responses.
    We suspect that these unusually vigorous T-cell responses to a first infection represent classical booster phenomena occurring in pre-existing populations of reactive T-lymphocytes.
    Could the idea that lymphocytes mediate cross-immunity to SARS-CoV-2 be
    The concept of lymphocyte-mediated herd immunity that we present follows from the integration of latest scientific data into the established context of host immunity to viral infections. The idea can actually be put to test. Thus, in a recent study, cynomolgus monkeys were successfully infected with SARSCoV-2. Although all animals shed the virus, not a single one fell ill. Minor lesions were found in the lungs of two animals, attesting to the fact that vigorous production of the virus had taken place. In essence, these findings replicated what has been witnessed in healthy humans. Repetition of the monkey experiment in animals depleted of lymphocytes would show whether herd immunity had indeed derived from the presence of the cells.”

(209) Jincun Zhao et al., “Airway Memory CD4+ T Cells Mediate Protective Immunity against Emerging
Respiratory Coronaviruses,” Immunity 44, no. 6 (June 2016): 1379–91,
(210) Annika Nelde et al., “SARS-CoV-2 T-cell Epitopes Define Heterologous and COVID-19-Induced TCell Recognition,” preprint, posted June 17, 2020,
(211) Alba Grifoni et al., “Targets of T-Cell Responses to SARS-CoV-2 Coronavirus in Humans with
COVID-19 Disease and Unexposed Individuals,” Cell 181, no. 7 (June 2020): 1489–501.e15, https://
(212) Takuya Sekine et al., “Robust T Cell Immunity in Convalescent Individuals with Asymptomatic or
Mild COVID-19,” Cell, (August 2020),

Excerpt from “Corona, False Alarm?” by prof. Sucharit Bhakdi e Dr. Karina Weiss


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