Author: Rowntree, Louise C; Petersen, Jan; Juno, Jennifer A; Chaurasia, Priyanka; Wragg, Kathleen; Koutsakos, Marios; Hensen, Luca; Wheatley, Adam K; Kent, Stephen J; Rossjohn, Jamie; Kedzierska, Katherine; Nguyen, Thi HO
Title: SARSâ€CoVâ€2â€specific CD8(+) Tâ€cell responses and TCR signatures in the context of a prominent HLAâ€A*24:02 allomorph Cord-id: coyz6wm5 Document date: 2021_6_4
ID: coyz6wm5
Snippet: Inâ€depth understanding of human T cellâ€mediated immunity in COVIDâ€19 is needed if we are to optimize vaccine strategies and immunotherapies. Identification of SARSâ€CoVâ€2 T cell epitopes and generation of peptideâ€HLA tetramers facilitates direct ex vivo analyses of SARSâ€CoVâ€2â€specific T cells and their T cell receptor (TCR) repertoires. We utilized a combination of peptide prediction and in vitro peptide stimulation to validate novel SARSâ€CoVâ€2 epitopes restricted by HLAâ€A
Document: Inâ€depth understanding of human T cellâ€mediated immunity in COVIDâ€19 is needed if we are to optimize vaccine strategies and immunotherapies. Identification of SARSâ€CoVâ€2 T cell epitopes and generation of peptideâ€HLA tetramers facilitates direct ex vivo analyses of SARSâ€CoVâ€2â€specific T cells and their T cell receptor (TCR) repertoires. We utilized a combination of peptide prediction and in vitro peptide stimulation to validate novel SARSâ€CoVâ€2 epitopes restricted by HLAâ€A*24:02, one of the most prominent HLA class I alleles, especially in Indigenous and Asian populations. Of the peptides screened, three spikeâ€derived peptides generated CD8(+)IFNâ€Î³(+) responses above background, S(1208â€1216) (QYIKWPWYI), S(448â€456) (NYNYLYRLF) and S(193â€201) (VFKNIDGYF), with S(1208) generating immunodominant CD8(+)IFNâ€Î³(+) responses. Using peptideâ€HLAâ€I tetramers, we performed direct ex vivo tetramer enrichment for HLAâ€A*24:02â€restricted CD8(+) T cells in COVIDâ€19 patients and preâ€pandemic controls. The precursor frequencies for HLAâ€A*24:02â€restricted epitopes were within the range previously observed for other SARSâ€CoVâ€2 epitopes for both COVIDâ€19 patients and preâ€pandemic individuals. Naïve A24/SARSâ€CoVâ€2â€specific CD8(+) T cells increased ~7.5â€fold above the average precursor frequency during COVIDâ€19, gaining effector and memory phenotypes. Ex vivo singleâ€cell analyses of TCRαβ repertoires found that the A24/S(448) (+)CD8(+) T cell TCRαβ repertoire was driven by a common TCRβ chain motif, while the A24/S(1208) (+)CD8(+) TCRαβ repertoire was diverse across COVIDâ€19 patients. Our study provides an in depth characterisation and important insights into SARSâ€CoVâ€2â€specific CD8(+) T cell responses associated with a prominent HLAâ€A*24:02 allomorph. This contributes to our knowledge on adaptive immune responses during primary COVIDâ€19 and could be exploited in vaccine or immunotherapeutic approaches.
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