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Delineating the role of co-stimulatory signals on human virus-specific memory CD8+ T cell activation and expansion using highly selective T cell receptor-targeted biologics

ABSTRACT: To delineate the minimum signals required to activate and expand antigen-specific memory CD8+ T cells, we recapitulated the discrete activation signals delivered by antigen-presenting cells using antigen-specific T-cell receptor-specific biologics termed Immuno-STAT (IST), which can specifically deliver a T cell receptor (TCR) signal alone or paired with a defined co-stimulatory signal to antigen-specific CD8+ T cells. Using a reductionist approach that provides defined TCR and co-stimulatory signaling, we demonstrated that different IST could engage TCR alone or in combination with either CD28 or 4-1BB to initiate distinct transcriptional programs in memory CMV-specific CD8+ T cells. As compared to activation by TCR signaling alone, the combination of TCR and CD28 or 4-1BB co-stimulatory signals significantly altered the transcriptome and drove expression of genes related to growth and survival. Nevertheless, TCR signaling in the presence of IL-2 (5 U/ml) was sufficient for robust recall activation and expansion of functional cytomegalovirus CMV(NLV)-specific and HIV(SL9)-specific memory CD8+ T cells. This response contrasts with naïve CD8+ T cells, which required CD28 co-stimulation in addition to TCR stimulation for antigen-specific activation and expansion even in the presence of high levels of IL-2 (100 U/ml). These results have important implications for antigen-specific immunotherapy by indicating that biologics that deliver TCR signals alone in the presence of IL-2 may be sufficient for immunotherapeutic strategies designed to expand memory CD8+ T cells to eliminate cancerous or infected cells. In contrast, strategies that aim to stimulate naïve T cell responses may benefit from the codelivery of TCR and CD28 signals.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312389 | GEO | 2025/12/08

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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Delineating the role of co-stimulatory signals on human virus-specific memory CD8+ T cell activation and expansion using highly selective T cell receptor-targeted biologics

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­­Delineating the role of co-stimulatory signals on human virus-specific memory CD8+ T cell activation and expansion using highly selective T cell receptor-targeted biologics

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OmicsDI is part of the ELIXIR infrastructure

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Delineating the role of co-stimulatory signals on human virus-specific memory CD8+ T cell activation and expansion using highly selective T cell receptor-targeted biologics