Spike protein suppresses immune synapse assembly in cytotoxic T lymphocytes, leading to impaired cytotoxicity and cytokine production

The Italian study investigated whether SARS-CoV-2, similar to viruses as HIV-1, can target immune synapse assembly and function to escape killing mediated by cytotoxic T lymphocytes. Their findings have shown that SARS-CoV-2 spike (S) protein suppresses immune synapse assembly in cytotoxic T lymphocytes, leading to impaired cytotoxicity and cytokine production.

T lymphocytes are responsible for the elimination of virally infected cells, and, therefore, cytotoxic T lymphocytes are strategic targets for immune escape by viral pathogens. Cytotoxic T lymphocyte-mediated killing of virally infected or malignant cells is orchestrated at the immune synapse, a highly specialized signaling and secretory platform at the lymphocytes interface with the target.

The S protein is crucial for understanding the molecular mechanisms of SARS-CoV-2 infection. The SARS-CoV-2 S protein consists of an S1 and an S2 subunit that are separated by host cell proteases. The S protein interacts not only with angiotensin-converting enzyme 2 (ACE2) receptors, but also with several other host receptors.

As the human ACE-2 receptor is expressed in activated T cells, and mediates SARS-CoV-2 binding and internalization, T lymphocytes can be directly modulated by the virus.

About the study

According to the authors, severe COVID-19 caused by SARS-CoV-2 is associated with T cell abnormalities which include lymphopenia and dysfunctions that range from excessive activation and exhaustion to defective activation and differentiation abnormalities. CD8+T cells appear preferentially dysregulated in severe COVID-19 compared to CD4+T cells. A decrease in cytokine production from CD8+T cells has been reported in severe cases of COVID-19, whereas the more robust expansion of CD8+T cells has been associated with milder disease or recovery.

The results of this study demonstrated that preincubation of cytotoxic T lymphocytes with the Wuhan or Omicron S protein variants led to the inhibition of the immune synapse assembly and its function. Consequently, cytotoxic T lymphocyte-mediated cytotoxicity and cytokine production were suppressed. This effect depends on interaction with the ACE-2 receptor, because the results were reversed by anti-S protein antibodies interfering with ACE-2 binding.

In addition, ex vivo results obtained in mononuclear cells from the bronchoalveolar lavage of 3 patients with acute COVID-19 showed that in vivo exposure of cytotoxic T lymphocytes to the S protein in the respiratory tract also compromises their capacity to form functional immune synapses.

The findings from this study revealed a new SARS-CoV-2 immune evasion strategy based on the S-protein dependent, ACE-2-mediated targeting of the lytic immune synapse to prevent elimination of infected cells.

This article was published in the scientific journal Journal of Experimental Medicine. Onnis A, et al. SARS-CoV-2 Spike protein suppresses CTL-mediated killing by inhibiting immune synapse assembly. J. Exp. Med. 2023 Vol. 220 No. 2 e20220906.