Dissecting the defects in the neonatal CD8+ T-cell response

Fike, Adam J; Kumova, Ogan K.; Carey, Alison J.

doi:10.1002/jlb.5ru0319-105r

Cited by 20 publications

(15 citation statements)

References 141 publications

(332 reference statements)

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“…Therapy can be initiated shortly after birth, and therefore near the time of transmission events occurring late in utero, during labor and delivery, or via breast milk -likely prior to the establishment of large populations of latently infected cells and the onset of immune dysregulation (22)(23)(24)(25). However, neonatal cytolytic immune cells have phenotypic and functional differences compared to the same cell populations in adults (26,27), and the impact of these differences on the activity of cytotoxic antibody-based immunotherapeutic drugs is not known. Thus, it is crucial to first evaluate infant passive immunotherapies in a model system that recapitulates the effector cells present in newborn infants.…”

Section: Introductionmentioning

confidence: 99%

Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules

et al. 2020

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Mother-to-child transmission of HIV-1 remains a major global health challenge. Currently, HIV-1-infected infants require strict lifelong adherence to antiretroviral therapy to prevent replication of virus from reservoirs of infected cells, and to halt progression of disease. There is a critical need for immune interventions that can be deployed shortly after infection to eliminate HIV-1-infected cells in order to promote long-term remission of viremia, or to potentially cure pediatric HIV-1-infection. Bispecific HIV × CD3 DART ® molecules able to co-engage the HIV-1 envelope protein on the surface of infected cells and CD3 on cytolytic T cells have been previously shown to eliminate HIV-1 infected cells in vitro and are candidates for passive immunotherapy to reduce the virus reservoir. However, their potential utility as therapy for infant HIV-1 infection is unclear as the ability of these novel antibody-based molecules to work in concert with cells of the infant immune system had not been assessed. Here, we use human umbilical cord blood as a model of the naïve neonatal immune system to evaluate the ability of HIV x CD3 DART molecules to recruit and redirect neonatal effector cells for elimination of autologous CD4 + T cells infected with HIV-1 encoding an envelope gene sequenced from a motherto-child transmission event. We found that HIV × CD3 DART molecules can redirect T cells present in cord blood for elimination of HIV-infected CD4 + T cells. However, we observed reduced killing by T cells isolated from cord blood when compared to cells isolated from adult peripheral blood-likely due to the absence of the memory and effector CD8 + T cells that are most cytolytic when redirected by bispecific DART molecules. We also found that newly developed HIV × CD16 DART molecules were able to recruit CD16-expressing natural killer cells from cord blood to eliminate HIV-infected cells, and the activity of cord blood natural killer cells could be substantially increased Pollara et al. DART-Molecule Recruitment of Neonatal Cells by priming with IL-15. Our results support continued development of HIV-specific DART molecules using relevant preclinical animal models to optimize strategies for effective use of this immune therapy to reduce HIV-1 infection in pediatric populations.

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Section: Introductionmentioning

confidence: 99%

Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules

et al. 2020

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“…Neonatal CD8 + T cells have unique characteristics that comply with the tolerance requirements of birth transition (6). However, they leave neonates highly susceptible to intracellular pathogen infections.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that neonatal CD8 + T cells have a unique transcriptomic and epigenetic signature, characterized by a lower expression of cytotoxic-and activation-related genes, and a bias toward innate immunity, particularly neutrophillike inflammation (10). A recent review summarizes the altered characteristics of neonatal CD8 + T cells (6).…”

Section: Introductionmentioning

confidence: 99%

IL-12 Signaling Contributes to the Reprogramming of Neonatal CD8+ T Cells

et al. 2020

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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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“…Although Th17 cells are discussed to be essential in children for mucocutaneous immunity especially against Candida and Staphylococcus in the respiratory tract and on the skin, and Th1 cells for protection against intracellular antigens, a balance of both seems to be optimal ( 13 ). In terms of CD8 + T-cell responses, they are suggested to not be generated properly before the age of two ( 14 , 15 ). Nevertheless, other associated studies suggest that infections, treatment with antibiotics as well as individual variations in immune development during childhood have long-term consequences to the prevalence of many diseases ( 16 – 18 ).…”

Section: Introductionmentioning

confidence: 99%

Children From the Age of Three Show a Developmental Switch in T-Cell Differentiation

et al. 2020

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Every sixth child suffers from hypertrophy of the adenoid, a secondary lymphoid organ, at least once in childhood. Little is known about the impact of pathogen-provocation vs. developmental impact on T-cell responses after 1 year of age. Therefore, developmental and infection-driven influences on the formation of T-cell-compartments and-multifunctionality in adenoids were analyzed taking into account patient's history of age and inflammatory processes. Here, we show that in adenoids of 102 infants and children similar frequencies of naïve, effector, and memory T-cells were accumulated, whereby history of suffering from subsequent infection symptoms resulted in lower frequencies of CD4 + and CD8 + T-cells co-expressing several cytokines. While patients suffering from sole nasal obstruction had balanced Th1-and Th17-compartments, Th1 dominated in patients with concomitant upper airway infections. In addition, analysis of cytokine co-expressing CD4 + and CD8 + T-cells showed that children at the age of three or older differed significantly from those being 1-or 2-years old, implicating a developmental switch in T-cell differentiation at that age. Yet, dissecting age and infectious history of the patients revealed that while CD8 + T-cell differentiation seems to be triggered by development, CD4 + T-cell functionality is partly impaired by infections. However, this functionality recovers by the age of 3 years. Thus, 3 years of age seems to be a critical period in an infant's life to develop robust T-cell compartments of higher quality. These findings identify important areas for future research and distinguish an age period in early childhood when to consider adjusting the choice of treatment of infections.

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Dissecting the defects in the neonatal CD8+ T-cell response

Cited by 20 publications

References 141 publications

Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules

Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules

IL-12 Signaling Contributes to the Reprogramming of Neonatal CD8+ T Cells

Children From the Age of Three Show a Developmental Switch in T-Cell Differentiation

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