IFN-ɣ derived from activated human CD4+ T cells inhibits the replication of SARS-CoV-2 depending on cell-type and viral strains.

Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection and vaccination induces T cell immunity as well as B cell responses in immunocompetent individuals. The mechanisms of anti-viral effect by CD4+ T cells as a part of T cell immunity are not fully understood. Here we used and analyzed the culture supernatant (SN) prepared from polyclonally stimulated human CD4+ T cells as a model of soluble mediator(s) from SARS-CoV-2-stimulated CD4+ T cells. Interestingly, this SN inhibited SARS-CoV-2 propagation in a viral strain- and host cell type-dependent manner. The most susceptible strain was original wild-type, and the insusceptible Delta strain in the case of human monocyte cell line. Antibody-dependent enhancement (ADE) of infection with original strain was also abolished in the presence of this SN. The following study revealed that the inhibitory effect against viral expansion by the SN was ascribed to interferon-ɣ (IFN-ɣ) included in SN, not to IFN-α, -β and -λ. These results highlight the important potential of IFN-ɣ as anti-SARS-CoV-2 mediator derived from CD4+ T cells and suggest that we need to understand the SARS-CoV-2 strain-dependent sensitivity against IFN-ɣ in controlling clinical manifestations. In addition, characterization of new SARS-CoV-2 variants in terms of IFN-ɣ-sensitivity will have important implications in selecting therapeutic strategy.