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Stem cell-like CD8+ T cells lacking PD-1 adapt to chronic stimulation by reducing TCR signaling and self-renewal capacity [scRNA-seq]

ABSTRACT: CD8+ T cells responding to chronic viral infection adapt to continuous antigenic stimulation by the upregulation of inhibitory receptors. Here we addressed how memory-like CD8+ T cells (TML), which sustain the immune response in chronic infection due to their stem cell-like properties, adapt to chronic stimulation when they cannot express the co-inhibitory receptor PD-1. We found that PD-1 deficient TML cells did not show evidence of a compensatory increases in the expression of other inhibitory receptors or exhaustion-related genes. Rather, these cells displayed a reduced ability to activate multiple signaling pathways downstream of the TCR. By-passing proximal TCR signaling events restored the activation of PD-1-deficient TML cells. Consistent with reduced TCR signaling, PD-1-deficient TML cells had a reduced ability to expand and self-renew in response to recall stimulation. Transient blockade of PD-1/PD-L1 interaction similarly reduced the stemness of TML cells. Thus, in the absence of PD-1, stem-like CD8+ T cells adapt to chronic stimulation by reducing the capacity of the TCR to transmit activating signals, which limits the stemness of these cells. Thus, PD-1 preserves the stemness of TML cells ensuring the long-term maintenance of the immune response to chronic infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE277649 | GEO | 2026/01/16

REPOSITORIES: GEO

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Project description:The inhibitory axis of PD-1 expressed on T cells and its ligands produced by APCs mediates T cell exhaustion in chronic viral infection. We asked whether temporality of the infectious process is decisive for regulation through PD-1/PD-Ligand and investigated its impact on chronic bacterial infection. Here we show that M. tuberculosis and its lipid compounds induce expression of PD-Ligand on dendritic cells (DC). Upregulation of PD-Ligand depended on signaling through DC-SIGN upon infection. As a counterpart, expression of the PD-1 receptor was increased on T cells from tuberculosis patients and PPD+ donors compared to healthy normal individuals. Moreover, PD-1 expressing T cells were confined to granulomatous lesions in tuberculous lungs. Finally, functional blocking of PD-Ligand rescued antigen-specific T cell responses of tuberculosis patients. Taken together, we demonstrate that the inhibitory axis of PD-1/PD-Ligand is operative in mycobacterial infection and suggest inhibition of inhibition for rescuing exhausted T cells in tuberculosis. Experiment Overall Design: Human PBMC-derived DCs were grown in 6-well plates and stimulated for 18 h with either mycobacterial ManLAM or recombinantly expressed ICAM-3. To ensure complete naÃ¯ve status of DCs before stimulation, cells were left in wells from the day of PBMC isolation until end of stimulation. Change of medium was performed by carefully removing medium from wells without any manipulation of DCs. After stimulation, total RNA was isolated as described above and labeled with Fluorescent Direct Labeling Kit (Agilent Technologies) following manufacturerâs protocols. Microarray experiments were performed as two-color dye-reversal hybridizations. To compensate for dye-specific effects, a color swap was performed. Labeled RNA was hybridized on Whole Human Genome Oligo Microarray Kit 44k Format and scanned using an Agilent scanner according to manufacturerâs protocol (Agilent Technologies). Image analysis was performed using Feature Extractor software (Agilent Technologies). For data analysis Rosetta Resolver software was used (Rosetta Inpharmatics).

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Stem cell-like CD8+ T cells lacking PD-1 adapt to chronic stimulation by reducing TCR signaling and self-renewal capacity [scRNA-seq]

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