Effects of IFN‐α as a signal‐3 cytokine on human naïve and antigen‐experienced CD8⁺ T cells

Abstract

IFN-α/β link innate and adaptive immune responses by directly acting on naïve CD8(+) T cells. This concept unveiled in mice remains unexplored in humans. To investigate that, human CD8(+) CD45RO(-) cells were stimulated with beads coated with anti-CD3 and anti-CD28 mAb, mimicking Ag (type-1) and co-stimulatory (type-2) signals, in the presence or absence of IFN-α and their transcriptional profiles were defined by cDNA-microarrays. We show that IFN-α provides a strong third signal directly to human CD8(+) T cells resulting in regulation of critical genes for their overall activation. This transcriptional effect was substantiated at the protein level and verified by functional assays. Interestingly, the biological effects derived from this stimulation vary depending on the CD8(+) T-cell population. Thus, whereas IFN-α increases the proliferative capacity of naïve CD8(+) T cells, it inhibits or does not affect the proliferation of Ag-experienced cells, such as memory and effector CTL, including CMV-specific lymphocytes. Cytolysis and IFN-γ-secretion of all these populations are enhanced by IFN-α-derived signals, which are critical in naïve CD8(+) T cells for acquisition of effector functions. Our findings in human CD8(+) T cells are informative to understand and improve IFN-α-based therapies for viral and malignant diseases.

A novel RNA‐based adjuvant combines strong immunostimulatory capacities with a favorable safety profile

“…[33][34][35] Thus, the ability of RNAdjuvant V R to induce high amounts of INF-a in vitro in hPBMCs and in vivo at the injection site in mice underlines its potential as a vaccine adjuvant. In addition to Type I IFN and Type I IFN-stimulated genes (ISGs) the adjuvant induced the upregulation of inflammasome-associated genes 36 such as IL-1b, which is described to be involved in lymphocyte activation and increased IL-12 secretion in dendritic cells.…”

CD8 T Cell Priming in the Presence of IFN-α Renders CTLs with Improved Responsiveness to Homeostatic Cytokines and Recall Antigens: Important Traits for Adoptive T Cell Therapy

“…Human CD45RA + CD27 high (naive), CD45RA +/2 CD27 2 (effector), CD45RA 2 CD27 + (memory) CD8 T cells were purified from PBLs eluted from leukocyte filters as Hervas-Stubbs and colleagues described previously (26). All blood donors gave written informed consent.…”

“…Samples of sorted cells and RNA extracted from them were frozen to be further analyzed, and naive CD8 T cells were cultured as follows. For polyclonal stimulation, CD8 T cells were cultured (5 3 10 5 cells/ml) with medium alone (RPMI 1640-glutamax medium [Invitrogen] supplemented with 10% FCS [Sigma] and 1% penicillin/ streptomycin [Invitrogen]) or medium containing IFN-a, anti-CD3/CD28 beads (Invitrogen) alone, or together with GMP-grade IFN-a (IFN-a 2b or IFN-a 5 ; Sicor Biotech UAB) (26). The IFN-a dose was 500 IU/ml.…”

“…We and others have shown that IL-12 and IFN-a also act directly on human naive CD8 T cells promoting the proliferation whereas favoring the acquisition of effector functions (25,26). However, there is scant information about the effects of innate inflammatory cytokines on the differentiation of human naive CD8 T cells into effector or memory CTLs.…”

Redirected T-Cell Killing of Solid Cancers Targeted with an Anti-CD3/Trop-2–Bispecific Antibody Is Enhanced in Combination with Interferon-α

“…Several reports identify CD8 þ T cells as direct targets of IFNa, affecting their IFNg production, survival, activation, clonal expansion, and memory differentiation (24)(25)(26)(27)(28)(29)(30)(31). IFNa provides a strong and direct signal to human CD8 þ T cells, thereby resulting in upregulation of critical genes for cytotoxic T-cell activity, and is absolutely critical in the case of human-naive CD8 þ T cells for effector function acquisition (26).…”