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GFI1-driven transcriptional and epigenetic programs maintain memory CD8+ T cell persistence [ATAC-seq].

ABSTRACT: CD8+ T cells play a pivotal role in restricting chronic virus infection and provide long-term protective immunity. The molecular mechanisms that govern long-term persistence of antiviral memory CD8+ T cells are poorly understood. Growth factor independent-1 (GFI1), a transcriptional repressor, plays a crucial role in T cell development. We show that following T cell activation, GFI1 expression is selectively maintained in memory CD8+ T cells, and GFI1 marks transcriptionally distinct antiviral CD8+ T cells with superior recall and expansion capacity. Conditional deletion of GFI1 in CD8+ T cells revealed that plays a crucial role in long-term persistence of CD8+ T cells responses following chronic virus infection. Single-cell multiome sequencing demonstrated that GFI1 epigenetically controls the gene regulatory networks that promote memory CD8+ T cell proliferation. GFI1 mediated eomesodermin expression protects the CD8+ T cells from activation induced cell death. Moreover, temporal mapping revealed that continuous GFI1 expression is required to maintain long-term memory CD8+ T cells persistence. Thus, GFI1 is central regulator of the molecular programs that shape memory features and is pivotal in promoting CD8+ T cell self-renewal and long-term protective memory formation.

ORGANISM(S): Mus musculus

PROVIDER: GSE271884 | GEO | 2025/04/23

REPOSITORIES: GEO

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Project description:The optimal T cell attributes for the adoptive immunotherapy of cancer and viral diseases are currently unclear. Recent adoptive transfer clinical trials using ex vivo expanded tumor infiltrating lymphocytes has provided evidence that differentiated effector T cells can mediate durable responses in selected cancer patients. The capacity of these transferred cells to persist in the host was found to strongly correlate with their clinical activity. Thus, there is significant interest in identifying intrinsic markers that define antigen specific effector T cells that can develop into long-lived memory cells rather than undergoing apoptosis after infusion in humans. We recently reported the long term persistence of ex vivo expanded tumor specific CD8+ T effector clones in refractory metastatic melanoma patients after adoptive T cell transfer. By utilizing these highly homogeneous clone populations, we sought to define the pre-infusion cellular and molecular attributes associated with their effector to memory transition. Comparative transcriptional profiling found the pre-infusion clone mRNA expression levels of the IL-7 receptor (IL-7Ra) and the proto-oncogene, c-myc, directly correlated with the level of clonal persistence after adoptive transfer in humans. The predictive value of these markers was further established by utilizing IL-7R protein, induced pSTAT5, and c-myc mRNA expression to prospectively identify human tumor specific effector clones that could engraft after controlled adoptive transfer into highly immunodeficient mice. These findings support that IL-7R and c-myc expression are valuable cell intrinsic markers that can predict the fate of effector CD8+ T cells after adoptive transfer. We used microarrays to compare the pre-infusion gene expression profile of melanoma-specific CD8+ T cell clones that would eventually either persist or not after adoptive transfer in humans. We derived ten melanoma-specific CD8+ T cell clones and determined their degree of persistence after adoptive therapy into patients. We performed microarray on the pre-infusion samples of six persisting and four non-persisting clones to obtain a comparative gene signature profile.

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GFI1-driven transcriptional and epigenetic programs maintain memory CD8+ T cell persistence [ATAC-seq].

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