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CD4 T lymphocytes from endemic coronaviruses could activate

SARS-CoV-2 has numerous similarities with endemic human coronaviruses (HCoV), which cause common infections. Several studies suggest that anti-HCoV immunity exists, capable of combatting SARS-CoV-2, although its role in the physiopathology of COVID-19 is unclear. This cross-immunity is hotly debated, but in the light of its importance for vaccination, it is crucial to better understand its role.

To this end, German researchers (at the Charité – University of Medicine and the Max Planck Institute in Berlin) have evaluated the reactivity of CD4 T lymphocytes in 60 healthy donors and 59 convalescing COVID-19 patients with multiple SARS-CoV-2 peptides (or protein fragments). In the healthy subjects, a weak but real CD4 T reactivity directed against the majority of viral peptides tested (including those corresponding to non-structural proteins) was detected, although CD4 T responses did vary from one individual to another.

In order to investigate more closely, and to target only anti-spike reactivity (which governs viral entry into the cell), the researchers iterated the experiment with 568 healthy donors and 174 convalescing COVID-19 patients, but this time using a pool of peptides from common pathogens and another pool of peptides corresponding to the SARS-CoV-2 spike. The S-II peptides, corresponding to the C-terminal part (residues 633 to 1273), have more homology to HCoV than the S-I peptides, corresponding to the N-terminal part (residues 1 to 643) of spike. It was clear that anti-S-II cross-reactivity is relatively frequent in healthy subjects, but diminishes with age, unlike the reactivity against other pathogens, which remains. The anti-S-I cross-reactivity I, however, virtually non-existent.

In healthy patients, a fraction of S-II-specific CD4 Tcells express less CD3 at their surface, which is characteristic of activated cells with high avidity, a very pronounced phenomenon in COVID-19 patients. Levels of these lymphocytes decrease with age, whether they react to HCoV or SARS-CoV-2. By crossing the reactivities of CD4 T cells with different SARS-CoV-2 or HCoV peptides, the researchers identified the immunodominant SFIEDLLFNKVTLAD peptide, located in the spike fusion domain. In a supplementary cohort of patients, 50% of convalescents and 20% of healthy subjects reacted to this peptide, which is mostly presented by CD38+ HLADR+ cells.

Further tests on 17 COVID-19 patients showed that these cross-reactive CD4 T cells are recruited, activated and amplified after an initial infection by SARS-CoV-2, which improves protection by neutralising antibodies. In 31 healthy patients vaccinated with Pfizer/BioNTech, the amplification of the pool of cross-reactive CD4 T cells correlated with a stronger humoral response and a faster cellular response.

The quantity and the avidity of cross-reactive CD4 T cells, deriving from previous, repeated infections by HCoVs, determine therefore the quality and the amplitude of anti-SARS-CoV-2 cellular and humoral responses. They limit the viral propagation and the severity of COVID-19. This pool of cells declines with age, which may explain why older people are more prone to developing serious illness. Vaccination efficiently amplifies these pre-existing CD4 T cells, which partly explains their effectiveness. These lymphocytes react effectively to the immunodominant peptide S816-830, which could therefore act as a universal target against coronaviruses.

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