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Single-cell RNA-sequencing of blood and tonsillar CD4+ CD57+ and CD57- T cells

ABSTRACT: Gene-environment interactions are implicated in immunopathology, but few specific mechanisms have been identified. We defined two terminal-differentiation pathways for human CD4+ T cells each marked by CD57. Rare blood CD57+ CD4+ T cells marked by TCF1 downregulation (Thcyt) adopt a cytotoxic and terminal-effector transcriptome. By contrast, human CD57+ GC-Tfh cells exhibit a transcriptome of the precursor exhausted T cells marked by TCF7, TOX and ID3 and constitutive expression of CTLA4, which collectively confer resistance to becoming cytotoxic. By clarifying human CD4+ T cell terminal differentiation, we have revealed how CTLA4 mitigates the risk of maladaptive cytotoxicity during infection.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200257 | GEO | 2023/04/27

REPOSITORIES: GEO

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Project description:T cells contribute to host-tumor interactions in patients with monoclonal gammopathies. Expansions of CD8+CD57+TCRVÎ²+ restricted cytotoxic T cell (CTL) clones are found in 48% of patients with multiple myeloma and confer a favorable prognosis. We now report the presence of CTL clones with varying TCRVÎ² repertoire in 70% of patients with Waldenstromâs Macroglobulinaemia (WM) (n=20). Previous nucleoside analogue (NA) therapy, associated with an increased incidence of transformation to aggressive lymphoma, significantly influenced the presence of TCRVÎ² expansions (X2=11.6; P<0.001) as 83% of patients without (n=6) and only 7% with TCRVÎ² expansions (n=14) had received NA. Clonality of CD3+CD8+CD57+TCRVÎ²+ restricted CTLs were confirmed by TCRVÎ² CDR3 size analysis and direct sequencing. To characterize CTL clones, samples of CD3+CD8+CD57+TCRVÎ²+ cells were profiled using DNA microarrays and the results were validated on both gene and protein level. By gene set enrichment analysis, CTL clones not only expressed genes (GZMB, PRF1, FGFBP2) from cytotoxic pathways but also genes which suppress apoptosis, inhibit proliferation, arrest cell cycle G1/S transition and activate T cells (RAS, CSK and TOB pathways). Proliferation tracking confirmed their anergic state. Our studies demonstrate the incidence, NA sensitivity and anergic nature of clonal T cells in a B cell tumor. We used microarrays to detail the global programme of gene expression underlying T cell clonal expansion and identified distinct classes of up-regulated genes during this process. Experiment Overall Design: In this study we have sought T cell clones in the blood of patients with WM and related their presence with nucleoside analog therapy and transformation. We have also sorted CD3+CD4-TCRVÎ²+CD57+ from CD3+CD4-TCRVÎ²+CD57- cells and confirmed clonality by TCRVÎ² CDR3 size determination and sequencing and used carboxy-fluorescein diacetate succinmidyl ester (CFSE) tracking to monitor proliferation of CD3+CD4-TCRVÎ²+CD57+ clones. Finally we have performed microarray analysis to search for significant differentially expressed genes and pathways in the clonally expanded CD3+CD8+TCRVÎ²+CD57+ cells, focusing on cytotoxic pathways but also identifying other dysfunctional changes in these cells. Expression of a selection of the most differentially expressed genes detected by microarray was validated at both gene (qPCR) and protein level.

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Single-cell RNA-sequencing of blood and tonsillar CD4+ CD57+ and CD57- T cells

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