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CITEseq analysis of human CSF cells in Multiple sclerosis

ABSTRACT: In CSF bulk RNA sequence, patients with MS (pwMS) exhibited higher T cell receprot (TCR) clonality and specificity to EBV lytic proteins compared to controls. TCRs from pwMS showed greater clustering coefficient (i.e. TCR similarity) in complementarity-determining regions 3 (CDR3), particularly those predicted to target EBV antigens. Importantly, TCR clustering coefficient was associated with the expression of cytotoxic CD8 module genes in WGCNA, such as CD8A, GZMH, GZMK, and NKG7 and with interferon signaling module. scRNA-seq revealed a subpopulation of GZMK+GZMH+ double positive (DP) CD8 T cells expressing genes related to identified cytotoxicity and interferon signaling modules. These DP CD8 T cells had significantly higher predicted specificity for EBV proteins than other CD8 cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286068 | GEO | 2025/02/01

REPOSITORIES: GEO

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Project description:The avidity of the T-cell receptor (TCR) for antigenic peptides presented by the MHC (pMHC) on cells is an essential parameter for efficient T cell-mediated immunity. Yet, whether the TCR-ligand avidity can drive the clonal evolution of virus antigen-specific CD8 T cells, and how this process is determined in latent Cytomegalovirus (CMV)- against Epstein-Barr virus (EBV)-mediated infection remains largely unknown. Here, we quantified monomeric TCR-pMHC dissociation rates on CMV- and EBV-specific individual TCR-alpha-beta clonotypes and polyclonal CD8 T cell populations in healthy donors over a follow-up time of 15-18 years. Within CMV/pp65-specific T cell repertoires, a progressive contraction of clonotypes with high TCR-pMHC avidity and low CD8 binding dependency was observed, leading to an overall avidity decline during long-term antigen exposure. We identified a unique transcriptional signature preferentially expressed by high-avidity CMV/pp65-specific T cell clonotypes, including the inhibitory receptor LILRB1. Interestingly, T cell clonotypes of high-avidity showed higher LILRB1 expression than the low-avidity ones and LILRB1 blockade moderately increased T cell proliferation. Similar findings were made for CD8 T cell repertoires specific for the CMV/IE-1 epitope. There was a gradual in vivo loss of high-avidity T cells with time for both CMV specificities, corresponding to virus-specific CD8 T cells expressing enhanced LILRB1 levels. In sharp contrast, the EBV/BMFL1-specific T cell clonal composition and distribution, once established, displayed an exceptional stability, unrelated to TCR-pMHC binding avidity or LILRB1 expression. Together, these findings reveal an overall long-term avidity decline of CMV- but not EBV-specific T cell clonal repertoires, highlighting the differing role played by TCR-ligand avidity over the course of these two latent herpesvirus infections. Our data suggest that the inhibitor receptor LILRB1 potentially restricts the clonal expansion of high-avidity CMV-specific T cell clonotypes during latent infection. We propose that the mechanisms regulating the long-term outcome of CMV- and EBV-specific memory CD8 T cell clonotypes in humans are distinct.

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	GSE286068_RAW.tar	Raw
	GSE286068_TotalseqB_reference_NDS_CSF_wHTO.csv.gz	Csv
	filelist.txt	Txt

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CITEseq analysis of human CSF cells in Multiple sclerosis

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