High frequencies of alpha common cold coronavirus/SARS-CoV-2 cross-reactive functional CD4+ and CD8+ memory T cells are associated with protection from symptomatic and fatal SARS-CoV-2 infections in unvaccinated COVID-19 patients

Abstract

Background: Cross-reactive SARS-CoV-2-specific memory CD4⁺ and CD8⁺ T cells are present in up to 50% of unexposed, pre-pandemic, healthy individuals (UPPHIs). However, the characteristics of cross-reactive memory CD4⁺ and CD8⁺ T cells associated with subsequent protection of asymptomatic coronavirus disease 2019 (COVID-19) patients (i.e., unvaccinated individuals who never develop any COVID-19 symptoms despite being infected with SARS-CoV-2) remains to be fully elucidated.

Methods: This study compares the antigen specificity, frequency, phenotype, and function of cross-reactive memory CD4⁺ and CD8⁺ T cells between common cold coronaviruses (CCCs) and SARS-CoV-2. T-cell responses against genome-wide conserved epitopes were studied early in the disease course in a cohort of 147 unvaccinated COVID-19 patients who were divided into six groups based on the severity of their symptoms.

Results: Compared to severely ill COVID-19 patients and patients with fatal COVID-19 outcomes, the asymptomatic COVID-19 patients displayed significantly: (i) higher rates of co-infection with the 229E alpha species of CCCs (α-CCC-229E); (ii) higher frequencies of cross-reactive functional CD134⁺CD137⁺CD4⁺ and CD134⁺CD137⁺CD8⁺ T cells that cross-recognized conserved epitopes from α-CCCs and SARS-CoV-2 structural, non-structural, and accessory proteins; and (iii) lower frequencies of CCCs/SARS-CoV-2 cross-reactive exhausted PD-1⁺TIM3⁺TIGIT⁺CTLA4⁺CD4⁺ and PD-1⁺TIM3⁺TIGIT⁺CTLA4⁺CD8⁺ T cells, detected both ex vivo and in vitro.

Conclusions: These findings (i) support a crucial role of functional, poly-antigenic α-CCCs/SARS-CoV-2 cross-reactive memory CD4⁺ and CD8⁺ T cells, induced following previous CCCs seasonal exposures, in protection against subsequent severe COVID-19 disease and (ii) provide critical insights into developing broadly protective, multi-antigen, CD4⁺, and CD8⁺ T-cell-based, universal pan-Coronavirus vaccines capable of conferring cross-species protection.

Keywords: SARS-CoV-2; CD4 + T cells; CD8 + T cells; COVID-19; asymptomatic; common cold coronavirus; exhaustion α-CCCs/SARS-CoV-2 cross-reactive T cells in asymptomatic COVID-19 infection; symptomatic.