CD4 T Cells Exhibit Distinct Transcriptional Phenotypes in the Lymph Nodes and Blood Following MRNA Vaccination in Humans

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mRNA vaccination induce robust CD4 T cell responses. Using single-cell transcriptomics, here, we evaluated CD4 T cells specific for the SARS-CoV-2 spike protein in the blood and draining lymph nodes (dLNs) of individuals 3 months and 6 months after vaccination with the BNT162b2 mRNA vaccine. We analyzed 1,277 spike-specific CD4 T cells, including 238 defined using Trex, a deep learning-based reverse epitope mapping method to predict antigen specificity. Human dLN spike-specific CD4 follicular helper T (T) cells exhibited heterogeneous phenotypes, including germinal center CD4 T cells and CD4IL-10 T cells. Analysis of an independent cohort of SARS-CoV-2-infected individuals 3 months and 6 months after infection found spike-specific CD4 T cell profiles in blood that were distinct from those detected in blood 3 months and 6 months after BNT162b2 vaccination. Our findings provide an atlas of human spike-specific CD4 T cell transcriptional phenotypes in the dLNs and blood following SARS-CoV-2 vaccination or infection.