High Frequencies of PD-1+TIM3+TIGIT+CTLA4+ Functionally Exhausted SARS-CoV-2-Specific CD4+ and CD8+ T Cells Associated with Severe Disease in Critically ill COVID-19 Patients

• Published in: bioRxiv 2022-01
• Main Authors: Coulon, Pierre-Gregoire A, Swayam Prakash, Dhanushkodi, Nisha R, Srivastava, Ruchi, Zayou, Latifa, Tifrea, Delia F, Edwards, Robert A, Figueroa, Cesar J, Schubl, Sebastian D, Hsieh, Lanny, Nesburn, Anthony B, Kuppermann, Baruch D, Bahraoui, Elmostafa, Vahed, Hawa, Gil, Daniel, Jones, Trevor M, Ulmer, Jeffrey B, Benmohamed, Lbachir
• Format: Article
• Language: English
• Subjects: Asymptomatic; CD134 antigen; CD4 antigen; CD8 antigen; Common cold; Coronaviruses; COVID-19; CTLA-4 protein; Epitopes; Genomes; Immunological memory; Infections; Leukocytosis; Lymphocytes; Lymphocytes T; Lymphopenia; Memory cells; PD-1 protein; Phenotypes; Severe acute respiratory syndrome coronavirus 2; γ-Interferon
• DOI: 10.1101/2022.01.30.478343

SARS-CoV-2-specific memory T cells that cross-react with common cold coronaviruses (CCCs) are present in both healthy donors and COVID-19 patients. However, whether these cross-reactive T cells play a role in COVID-19 pathogenesis versus protection remain to be fully elucidated. In this study, we characterized cross-reactive SARS-CoV-2-specific CD4+ and CD8+ T cells, targeting genome-wide conserved epitopes in a cohort of 147 non-vaccinated COVID-19 patients, divided into six groups based on the degrees of disease severity. We compared the frequency, phenotype, and function of these SARS-CoV-2-specific CD4+ and CD8+ T cells between severely ill and asymptomatic COVID-19 patients and correlated this with alpha-CCCs and beta-CCCs co-infection status. Compared with asymptomatic COVID-19 patients, the severely ill COVID-19 patients and patients with fatal outcomes: (i) Presented a broad leukocytosis and a broad CD4+ and CD8+ T cell lymphopenia; (ii) Developed low frequencies of functional IFN-gamma-producing CD134+CD138+CD4+ and CD134+CD138+CD8+ T cells directed toward conserved epitopes from structural, non-structural and regulatory SARS-CoV-2 proteins; (iii) Displayed high frequencies of SARS-CoV-2-specific functionally exhausted PD-1+TIM3+TIGIT+CTLA4+CD4+ and PD-1+TIM3+TIGIT+CTLA4+CD8+ T cells; and (iv) Displayed similar frequencies of co-infections with beta-CCCs strains but significantly fewer co-infections with alpha-CCCs strains. Interestingly, the cross-reactive SARS-CoV-2 epitopes that recalled the strongest CD4+ and CD8+ T cell responses in unexposed healthy donors (HD) were the most strongly associated with better disease outcome seen in asymptomatic COVID-19 patients. Our results demonstrate that, the critically ill COVID-19 patients displayed fewer co-infection with alpha-CCCs strain, presented broad T cell lymphopenia and higher frequencies of cross reactive exhausted SARS-CoV-2-specific CD4+ and CD8+ T cells. In contrast, the asymptomatic COVID-19 patients, appeared to present more co-infections with alpha-CCCs strains, associated with higher frequencies of functional cross-reactive SARS-CoV-2-specific CD4+ and CD8+ T cells. These findings support the development of broadly protective, T-cell-based, multi-antigen universal pan-Coronavirus vaccines. Competing Interest Statement The authors have declared no competing interest.