Immune-checkpoint blockade of CTLA-4 (CD152) in antigen-specific human T-cell responses differs profoundly between neonates, children, and adults

Arra, Aditya; Pech, M; Fu, Hang; Lingel, Holger; Braun, Franziska; Beyer, Christian; Spiliopoulou, Myra; Bröker, Barbara M.; Lampe, Karen; Arens, Christoph; Vogel, Katrin; Pierau, Mandy; Brunner‐Weinzierl, Monika C.

doi:10.1080/2162402x.2021.1938475

Cited by 4 publications

(6 citation statements)

References 54 publications

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“…2c , Table S7 ) was detectable in all S. aureus stimulated T-cells. In extension to a published study of total CD4 + T-cells 3 , experiments were performed using naïve T-cells. The accumulation/secretion of IFN-γ was three times higher in supernatants of S. aureus -simulated T-cells of donors being 6 years and older compared to 0–5-year-olds (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…A child faces the greatest probability of dying within the first 28 days after birth, followed by the first 5 years of life 1 , 2 . Although studies have shown that the immune system early in life reacts differently compared to that of adults, the developmental-specific mechanisms of triggering an antibacterial response and avoiding an adverse reaction are yet not completely understood 3 – 7 . Recently, a predetermined developmental trajectory of the composition of the cell populations in blood during the first 3 months of life was reported; however, data thereafter and functional characteristics of these cells are not addressed in depth 8 , 9 .…”

Section: Introductionmentioning

confidence: 99%

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Bifidobacteria shape antimicrobial T-helper cell responses during infancy and adulthood

Vogel,

Arra,

Lingel

et al. 2023

Nat Commun

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Microbial infections early in life are challenging for the unexperienced immune system. The SARS-CoV-2 pandemic again has highlighted that neonatal, infant, child, and adult T-helper(Th)-cells respond differently to infections, and requires further understanding. This study investigates anti-bacterial T-cell responses against Staphylococcus aureus aureus, Staphylococcus epidermidis and Bifidobacterium longum infantis in early stages of life and adults and shows age and pathogen-dependent mechanisms. Beside activation-induced clustering, T-cells stimulated with Staphylococci become Th1-type cells; however, this differentiation is mitigated in Bifidobacterium-stimulated T-cells. Strikingly, prestimulation of T-cells with Bifidobacterium suppresses the activation of Staphylococcus-specific T-helper cells in a cell-cell dependent manner by inducing FoxP3+CD4+ T-cells, increasing IL-10 and galectin-1 secretion and showing a CTLA-4-dependent inhibitory capacity. Furthermore Bifidobacterium dampens Th responses of severely ill COVID-19 patients likely contributing to resolution of harmful overreactions of the immune system. Targeted, age-specific interventions may enhance infection defence, and specific immune features may have potential cross-age utilization.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bifidobacteria shape antimicrobial T-helper cell responses during infancy and adulthood

Vogel,

Arra,

Lingel

et al. 2023

Nat Commun

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“…To specifically compare the properties of antigen-inexperienced CD4 T-cells, the naïve (CD45RA) CD25 neg CD4 T-cells of neonates (nT N ) and adults (T N ) were enriched in addition to the memory (CD45RO) CD25 neg CD4 T-cells (T M ) using MACS [ 14 ]. The enriched CD4 T-cells were treated with PD-1- and PD-L1-blocking antibodies or isotype controls and were either allowed to rest or stimulated with SEB or with S. aureus -loaded autologous monocytes and analyzed 3 and 5 days after the onset of stimulation, respectively ( Figure 1 a) [ 21 , 25 ]. An up-regulation of the TCR-signaling induced surface molecule CD69 was monitored upon the SEB and S. aureus encounter but not in the resting conditions of co-cultures of CD4 T-cells with unloaded monocytes ( Figure 1 b,c).…”

Section: Resultsmentioning

confidence: 99%

“…The monocytes were matured with h.i. S. aureus with no expression of the Staphylococcal enterotoxin B (SEB neg ) [ 25 ]. In brief, the monocytes were pulsed with 10 µg/mL S. aureus in a complete RPMI1640 medium (PAN BioTech) for 24 h at 37 °C/5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Here, a model for human antibacterial T-cell responses was applied [ 21 , 25 ] that allowed us to decipher the characteristics of human neonatal T-cell responses and differentiation in an antigen-specific manner. The antibody mediated blockade of the co-inhibitory receptor PD-1 and its ligand PD-L1 revealed an immediate and tight control of neonatal T-helper cell responses by these immune-checkpoint molecules.…”

Section: Introductionmentioning

confidence: 99%

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PD-1/PD-L1 Control of Antigen-Specifically Activated CD4 T-Cells of Neonates

Majer

Lingel

Arra

et al. 2023

IJMS

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Newborns are highly susceptible to infections; however, the underlying mechanisms that regulate the anti-microbial T-helper cells shortly after birth remain incompletely understood. To address neonatal antigen-specific human T-cell responses against bacteria, Staphylococcus aureus (S. aureus) was used as a model pathogen and comparatively analyzed in terms of the polyclonal staphylococcal enterotoxin B (SEB) superantigen responses. Here, we report that neonatal CD4 T-cells perform activation-induced events upon S. aureus/APC-encounter including the expression of CD40L and PD-1, as well as the production of Th1 cytokines, concomitant to T-cell proliferation. The application of a multiple regression analysis revealed that the proliferation of neonatal T-helper cells was determined by sex, IL-2 receptor expression and the impact of the PD-1/PD-L1 blockade. Indeed, the treatment of S. aureus-activated neonatal T-helper cells with PD-1 and PD-L1 blocking antibodies revealed the specific regulation of the immediate neonatal T-cell responses with respect to the proliferation and frequencies of IFNγ producers, which resembled in part the response of adults’ memory T-cells. Intriguingly, the generation of multifunctional T-helper cells was regulated by the PD-1/PD-L1 axis exclusively in the neonatal CD4 T-cell lineage. Together, albeit missing memory T-cells in neonates, their unexperienced CD4 T-cells are well adapted to mount immediate and strong anti-bacterial responses that are tightly controlled by the PD-1/PD-L1 axis, thereby resembling the regulation of recalled memory T-cells of adults.

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Informing immunotherapy with multi-omics driven machine learning

Li,

Wu,

Fang

et al. 2024

npj Digit. Med.

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Progress in sequencing technologies and clinical experiments has revolutionized immunotherapy on solid and hematologic malignancies. However, the benefits of immunotherapy are limited to specific patient subsets, posing challenges for broader application. To improve its effectiveness, identifying biomarkers that can predict patient response is crucial. Machine learning (ML) play a pivotal role in harnessing multi-omic cancer datasets and unlocking new insights into immunotherapy. This review provides an overview of cutting-edge ML models applied in omics data for immunotherapy analysis, including immunotherapy response prediction and immunotherapy-relevant tumor microenvironment identification. We elucidate how ML leverages diverse data types to identify significant biomarkers, enhance our understanding of immunotherapy mechanisms, and optimize decision-making process. Additionally, we discuss current limitations and challenges of ML in this rapidly evolving field. Finally, we outline future directions aimed at overcoming these barriers and improving the efficiency of ML in immunotherapy research.

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Immune-checkpoint blockade of CTLA-4 (CD152) in antigen-specific human T-cell responses differs profoundly between neonates, children, and adults

Abstract: 2021) Immune-checkpoint blockade of CTLA-4 (CD152) in antigen-specific human T-cell responses differs profoundly between neonates,

Cited by 4 publications

References 54 publications

Bifidobacteria shape antimicrobial T-helper cell responses during infancy and adulthood

Bifidobacteria shape antimicrobial T-helper cell responses during infancy and adulthood

PD-1/PD-L1 Control of Antigen-Specifically Activated CD4 T-Cells of Neonates

Informing immunotherapy with multi-omics driven machine learning

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