To better understand why human neonates show a poor response to intracellular pathogens, we compared gene expression and histone modification profiles of neonatal naive CD8 T cells with that of their adult counterparts. We found that neonatal lymphocytes have a distinct epigenomic landscape associated with a lower expression of genes involved in T cell receptor (TCR) signaling and cytotoxicity and a higher expression of genes involved in the cell cycle and innate immunity. Functional studies corroborated that neonatal CD8 T cells are less cytotoxic, transcribe antimicrobial peptides, and produce reactive oxygen species. Altogether, our results show that neonatal CD8 T cells have a specific genetic program biased toward the innate immune response. These findings will contribute to better diagnosis and management of the neonatal immune response.

CD4+ T cells recognize antigens through their T cell receptors (TCRs); however, additional signals involving costimulatory receptors, for example, CD28, are required for proper T cell activation. Alternative costimulatory receptors have been proposed, including members of the Toll-like receptor (TLR) family, such as TLR5 and TLR2. To understand the molecular mechanism underlying a potential costimulatory role for TLR5, we generated detailed molecular maps and logical models for the TCR and TLR5 signaling pathways and a merged model for cross-interactions between the two pathways. Furthermore, we validated the resulting model by analyzing how T cells responded to the activation of these pathways alone or in combination, in terms of the activation of the transcriptional regulators CREB, AP-1 (c-Jun), and NF-κB (p65). Our merged model accurately predicted the experimental results, showing that the activation of TLR5 can play a similar role to that of CD28 activation with respect to AP-1, CREB, and NF-κB activation, thereby providing insights regarding the cross-regulation of these pathways in CD4+ T cells.

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.

The canonical Wnt signaling pathway is a master cell regulator involved in CD8+ T cell proliferation and differentiation. In human CD8+ T cells, this pathway induces differentiation into memory cells or a “stem cell memory like” population, which is preferentially present in cord blood. To better understand the role of canonical Wnt signals in neonatal or adult blood, we compared the proteins associated with β‐catenin, in nonstimulated and Wnt3a‐stimulated human neonatal and adult naive CD8+ T cells. Differentially recruited proteins established different complexes in adult and neonatal cells. In the former, β‐catenin‐associated proteins were linked to cell signaling and immunological functions, whereas those of neonates were linked to proliferation and metabolism. Wnt3a stimulation led to the recruitment and overexpression of Wnt11 in adult cells and Wnt5a in neonatal cells, suggesting a differential connexion with planar polarity and Wnt/Ca2+ noncanonical pathways, respectively. The chromatin immunoprecipitation polymerase chain reaction β‐catenin was recruited to a higher level on the promoters of cell renewal genes in neonatal cells and of differentiation genes in those of adults. We found a preferential association of β‐catenin with CBP in neonatal cells and with p300 in the adult samples, which could be involved in a higher self‐renewal capacity of the neonatal cells and memory commitment in those of adults. Altogether, our results show that different proteins associated with β‐catenin during Wnt3a activation mediate a differential response of neonatal and adult human CD8+ T cells.

Birth causes complex changes in the individual physiology and organ systems and certainly poses a big immune challenge. The sudden encounter with an antigen full world, with the exposure to food antigens, and the colonization of the skin and mucosa with microbiota, require a tolerant immune system. Nevertheless, neonates must also be able to deal with pathogens, which makes their immune system unique. T lymphocytes are responsible for the coordination of the adaptive immune system response, the elimination of infected cells and the type of immune response and memory. It has been shown that neonatal cells have intrinsic differences with adult cells, biased towards an innate response and a tolerant phenotype. In the perinatal period, the immune system changes from basal signaling and innate like responses, towards stimulus-specific signals, which increase with gestational age. After birth the cells of the immune system continue to change both in composition and function. In this review, we present the intrinsic differences of neonatal CD4+ and CD8+ T cells, as compared with adult naïve cells. A specific transcriptome profile is present in both CD4+ and CD8+ neonatal T cells, with overexpression of homeobox transcription factors. These cells also present differences in cell signaling and metabolic characteristics, which result in unique functional capabilities. Neonatal CD4+ T cells respond differently from adult cells, with a high production of IL-8, a prevalent Th2 over Th1 profile, and an innate inflammatory response. The neonatal period is one of the most vulnerable periods of life, with a high morbidity and mortality rate, approaching on average 17 deaths per 1000 live births worldwide. A better understanding of the neonatal immune system will help to ensure a better care of this vulnerable population.