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IL-12 Signaling Contributes to the Reprogramming of Neonatal CD8+ T Cells
Darely Y Gutiérrez-Reyna1, Alejandra Cedillo-Baños1, Linda A Kempis-Calanis1
1Centro de Investigación en Dinámica Celular (IICBA), Universidad Autónoma del Estado de Morelos, Cuernavaca, Mexico.
Insights
Interleukin-12 (IL-12) signals help reprogram neonatal CD8+ T cells, improving their function and response to infections. This finding is crucial for developing better neonatal vaccines and treatments.
Area of Science:
- Immunology
- Neonatal immunology
- Cellular immunology
Background:
- Neonates exhibit heightened susceptibility to intracellular pathogens, contributing to significant morbidity and mortality.
- CD8+ T lymphocytes are critical for clearing infected cells, but their function in neonates is not fully understood.
- Previous research indicated neonatal CD8+ T cells have elevated innate inflammatory gene expression and reduced cytotoxic/signaling gene expression.
Purpose of the Study:
- To investigate the activation potential and transcriptional changes in human neonatal and adult naive CD8+ T cells.
- To evaluate the impact of T-cell receptor/CD28 stimulation with or without IL-12 on these cells.
- To understand how IL-12 influences the epigenetic landscape and gene expression profiles of neonatal CD8+ T cells.
Main Methods:
- Transcriptome analysis of neonatal and adult naive CD8+ T cells after stimulation.
- Quantitative reverse transcription PCR (RT-qPCR) to validate gene expression changes.
- Analysis of promoter methylation status to assess epigenetic modifications.
Main Results:
- IL-12 signaling promoted adult-like expression of genes related to cell signaling, T-cell cytokines, metabolism, and cell division in neonatal cells.
- IL-12 downregulated the neutrophil transcription factor CEBPE and other immaturity-associated genes in neonatal CD8+ T cells.
- IL-12 induced epigenetic changes, including chromatin closure of neutrophil-like genes and opening of cytotoxicity genes, suggesting reprogramming.
Conclusions:
- IL-12 plays a significant role in the epigenetic reprogramming of neonatal CD8+ T lymphocytes.
- These findings highlight IL-12's potential to enhance neonatal immune responses for improved therapeutic and vaccine strategies.
- Neonatal CD8+ T cells retain a high inflammatory profile even after stimulation, consistent with the neonatal inflammatory response to infections.
Abstract:
Neonates are highly susceptible to intracellular pathogens, leading to high morbidity and mortality rates. CD8+ T lymphocytes are responsible for the elimination of infected cells. Understanding the response of these cells to normal and high stimulatory conditions is important to propose better treatments and vaccine formulations for neonates. We have previously shown that human neonatal CD8+ T cells overexpress innate inflammatory genes and have a low expression of cytotoxic and cell signaling genes. To investigate the activation potential of these cells, we evaluated the transcriptome of human neonatal and adult naïve CD8+ T cells after TCR/CD28 signals ± IL-12. We found that in neonatal cells, IL-12 signals contribute to the adult-like expression of genes associated with cell-signaling, T-cell cytokines, metabolism, and cell division. Additionally, IL-12 signals contributed to the downregulation of the neutrophil signature transcription factor CEBPE and other immaturity related genes. To validate the transcriptome results, we evaluated the expression of a series of genes by RT-qPCR and the promoter methylation status on independent samples. We found that in agreement with the transcriptome, IL-12 signals contributed to the chromatin closure of neutrophil-like genes and the opening of cytotoxicity genes, suggesting that IL-12 signals contribute to the epigenetic reprogramming of neonatal lymphocytes. Furthermore, high expression of some inflammatory genes was observed in naïve and stimulated neonatal cells, in agreement with the high inflammatory profile of neonates to infections. Altogether our results point to an important contribution of IL-12 signals to the reprogramming of the neonatal CD8+ T cells.
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