T cell response to intact SARS-CoV-2 includes coronavirus cross-reactive and variant-specific components

Abstract

SARS-CoV-2 provokes a brisk T cell response. Peptide-based studies exclude antigen processing and presentation biology and may influence T cell detection studies. To focus on responses to whole virus and complex antigens, we used intact SARS-CoV-2 and full-length proteins with DC to activate CD8 and CD4 T cells from convalescent persons. T cell receptor (TCR) sequencing showed partial repertoire preservation after expansion. Resultant CD8 T cells recognize SARS-CoV-2-infected respiratory cells, and CD4 T cells detect inactivated whole viral antigen. Specificity scans with proteome-covering protein/peptide arrays show that CD8 T cells are oligospecific per subject and that CD4 T cell breadth is higher. Some CD4 T cell lines enriched using SARS-CoV-2 cross-recognize whole seasonal coronavirus (sCoV) antigens, with protein, peptide, and HLA restriction validation. Conversely, recognition of some epitopes is eliminated for SARS-CoV-2 variants, including spike (S) epitopes in the alpha, beta, gamma, and delta variant lineages.

T cell receptor sequencing identifies prior SARS-CoV-2 infection and correlates with neutralizing antibodies and disease severity

“…AIM-based enrichment of SARS-CoV-2-specific T cells was performed using PBMCs from 2 independent convalescent samples from each of 3 convalescent individuals from the original study population. Samples from these 3 individuals (patients W001, W005, and W012) were selected based on their inclusion in a data set used for T cell epitope discovery in a separate study (51). Each of these 3 patients required hospitalization and intensive care admission for treatment of COVID-19.…”

“…Each of these 3 patients required hospitalization and intensive care admission for treatment of COVID-19. PBMCs were stimulated with whole, ultraviolet light-killed, cell-associated SARS-CoV-2 with inclusion of autologous monocyte-derived DCs (moDC), as recently described (51,52). In brief, SARS-CoV-2 strain WA1 was expanded in Vero-E6 cells transfected with angiotensin-converting enzyme-2 (ACE2) and transmembrane serine protease 2 (TMPRSS2; gifted by Michael Diamond, Washington University, St. Louis, Missouri, USA).…”

The prospect of universal coronavirus immunity: a characterization of reciprocal and non-reciprocal T cell responses against SARS-CoV2 and common human coronaviruses

“…Cross-recognition of counterpart antigens from non-SARS hCoVs and SARS-CoV2 was seen in some donors, often displaying unidirectional/non-reciprocal pattern. Namely, T cells initially primed to recognize hCoV antigens were more cross-reactive, whereas priming with SARS-CoV2 antigens induced minimally cross-reactive populations, likely indicating focused immunological memory skewed towards non-shared dominant epitopes[56]. TCR sequencing of highly purified antigen-specific T cells isolated from two COVID-19 survivors elucidates the basis of this observation, revealing dominant clonotypes shared between α or β-hCoV-reactive populations, while SARS-CoV2-specific T cells contained distinct repertoires.…”

“…In parallel, we studied reactivity against the endemic hCoV, observing immune responses in the majority of healthy and immunocompromised subjects. Interestingly, COVID-19 survivors displayed a broader reactivity pattern against the endemic viruses, suggesting possible induction of cross-reactive immunity upon resolution of COVID-19 that is increasingly recognized in literature [56,57]. Ex vivo expanded T cells specific for SARS-CoV2 S, M and NP antigens and the equivalent antigens from hCoVs were further tested for cross-reactivity.…”