Viral control by a unique cytotoxic SARS-CoV-2 spike protein-specific CD4+ T cell population

ABSTRACT: Little is known of the role of cytotoxic CD4+ T-cells (CTLs) in the control of human viral replication. Here, we investigate CD4+ T-cell responses to three immunodominant SARS-CoV-2 epitopes identified in our study cohort, and evaluate cytotoxic activity and antiviral cytokine production in response to virus infected cells together with changes in the transcriptome and proteome of CD4+ CTLs. We found S866-880-specific CD4+ T-cells exhibit the highest cytotoxicity, which correlated with the strongest anti-viral efficacy; moreover, this was independent of TCR usage or IL-2 production. CD4+ CTLs exhibited distinct signalling and cytotoxic pathways compared to classical CD8+ T-cells, with increased expression of GZMM and GZMK, together with chemokines and tissue homing receptors promoting migration. Furthermore, CD4+ CTLs showed decreased expression of KYNU, IDO1 and SOD2 implicating a dampening of Treg-mediated suppression of CD4+ effector function. We also found diverse T cell receptor (TCR) usage including an unexpected high level of public TCR usage among all three epitope specific T cells; however, this did not correlate with cytotoxicity or functional avidity. Our study suggested unique features of cytotoxic CD4+ T-cells, implicating distinct functional pathways, which could play an important role in viral control of memory T cell responses induced by infection or vaccination.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Severe Acute Respiratory Syndrome Coronavirus 2

TISSUE(S): T Cell, Pbmc Cell Line

SUBMITTER: iolanda Vendrell  

LAB HEAD: Tao Dong

PROVIDER: PXD042469 | Pride | 2025-08-15

REPOSITORIES: Pride