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.
Highlights
The neonate population is at high risk of infection by intracellular pathogens, which cause severe diseases and a high mortality rate [1]
In agreement with our previous report, in which we showed that neonatal cells had a higher homeostatic proliferation and were biased toward neutrophil-like inflammation [10], we found that pathways in neonatal cells were biased toward cell cycle and innate immunity (Supplementary Figure 1)
TCR stimulated genes in adult cells were associated with immune response, while those of neonates were still biased toward cell cycle and IL-10 signaling (Figure 1B), in agreement with the tolerant phenotype of neonatal cells
Summary
The neonate population is at high risk of infection by intracellular pathogens, which cause severe diseases and a high mortality rate [1]. CD8+ T cells are responsible for the elimination of dysfunctional, infected, or stressed cells through antigen-dependent mechanisms. To induce cytotoxic T lymphocyte-mediated immunity, antigen recognition must occur in the context of co-stimulation and pro-inflammatory cytokines, interleukin (IL)-12 or IFNα/β [3]. Both cytokines induce the activation and differentiation of CD8+ T cells into effector cells, IL-12 signals induced the expression of a larger number of genes, a higher level of IFNγ, and was able to restore the functionality of exhausted T cells [3,4,5]
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