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The effector program of human CD8 T cells can promote both target cell killing and tissue remodeling (MRC5)

ABSTRACT: CD8 T lymphocytes are classically viewed as cytotoxic T cells. Whether human CD8 T cells can, in parallel, induce a regenerative program is not completely understood. Here, we have studied antigen-specific assay systems, which revealed that human CD8 T cells not only mediated cytotoxicity, but also promoted bystander fibroblast and epithelial cell activation, leading to the production of tissue regenerative factors such as Amphiregulin (Areg). Tissue remodeling could be inhibited by blocking the epidermal growth factor receptor or the effector cytokines IFN- and TNF. Using single-cell chromatin accessibility and gene expression analysis, we identified a tissue-resident CD8 T cell population in healthy donor skin and adipose tissue with an effector program promoting Areg, TNF and IFNg expression, and a TCR-linkage analysis demonstrated a strong clonal relation between tissue and blood PD1+TIGIT+TOX+ CD8 T cells with tissue remodeling abilities. This regenerative program was also present in anti-cancer associated CD8 populations including chimeric antigen receptor (CAR) CD8 T cells. Once activated, the tissue regenerative program of human CD8 T cells enhanced tumor spheroid, as well as primary liver/bile duct organoid growth. Our findings may help to understand the conflicting CD8 biology in the tumor micromilieu and become relevant for the design of CD8 T-cell therapies for solid tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE223987 | GEO | 2023/11/20

REPOSITORIES: GEO

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Project description:Immune memory cells are poised to rapidly expand and elaborate effector functions upon reinfection. However, despite heightened readiness to respond, memory cells exist in a functionally quiescent state. The paradigm is that memory cells remain inactive due to lack of TCR stimuli. Here we report a unique role of Tregs in orchestrating memory quiescence by inhibiting effector and proliferation programs through CTLA-4. Loss of Tregs resulted in activation of genome-wide transcriptional programs characteristic of potent effectors, and both developing and established memory quickly reverted to a terminally differentiated (KLRG-1hi/IL-7R±lo/GzmBhi) phenotype, with compromised metabolic fitness, longevity, polyfunctionality and protective efficacy. CTLA-4, an inhibitory receptor overexpressed on Tregs, functionally replaced Tregs in trans to rescue Treg-less memory defects and restore homeostasis of secondary mediators as well. These studies present CD28-CTLA-4-CD80/CD86 axis as a novel target to potentially accelerate vaccine-induced immunity and improve T-cell memory quality in current cancer immunotherapies proposing transient Treg-depletion. We used microarray analysis to detail the global programming of gene expression in LCMV GP33-specific CD8 T cells differentiated in the presence or absence of regulatory T cells Differentiation of memory CD8 T cells entails a progressive transition of highly activated effector program to a quiescent memory program. A key question in the field is to understand the factors that aid in the differentiation of memory cells from effector cells. It is a generally accepted paradigm that effector cells transition to a memory state by default after antigen clearance, since TCR stimuli is the key driver of effector programs in CD8 T cells. We hypothesized that the effector to memory transition of CD8 T cells involves active immunological brakes through regulatory T cells (Tregs) that allow the highly activated effector cells to convert into quiescent memory cells. To address this hypothesis, we used FoxP3-DTR mice to deplete Tregs during the window following antigen clearance, during which the effector CD8 T cells convert to long-lived memory cells. To get a deeper understanding of the global transcriptome of CD8 T cells as they transition from an effector to a memory state, we isolated and arrayed the antigen-specific CD8 T cells at day 16 post-infection that have experienced the transitional environment with and without the presence of Tregs.

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The effector program of human CD8 T cells can promote both target cell killing and tissue remodeling (MRC5)

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