Biology subjects

Guyer, R.

Publications and source records attributed to Guyer, R..

3 recordsLinked to original sources

bioRxiv2025

Transcriptional control of T cell tissue adaptation and effector function in infants and adults

The first years of life are essential for the development of memory T cells, which rapidly populate the bodys diverse tissue sites during infancy. However, the degree to which tissue memory T cell responses in early life reflect those during adulthood is unclear. Here, we use single cell RNA-sequencing of resting and ex vivo activated T cells from lymphoid and mucosal tissues of infant (aged 2-9 months) and adult (aged 40-65 years) human organ donors to dissect the transcriptional programming of memory T cells over age. Infant memory T cells demonstrate a unique stem-like transcriptional profile and tissue adaptation program, yet exhibit reduced activation capacity and effector function relative to adults. Using CRISPR-Cas9 knockdown, we define Helios (IKZF2) as a critical transcriptional regulator of the infant-specific tissue adaptation program and restricted effector state. Our findings reveal key transcriptional mechanisms that control tissue T cell fate and function in early life.

immunology↗

bioRxiv2024

Dietary iron deficiency impairs effector function of memory T cells following influenza infection

The establishment of memory T cell responses is critical to protection against pathogens and is influenced by the conditions under which memory formation occurs. Iron is an essential micronutrient for multiple immunologic processes and nutritional deficiency is a common problem worldwide. Despite its prevalence, the impact of nutritional iron deficiency on the establishment of memory T cell responses is not fully understood. In this study we investigate the impact of nutritional iron deficiency on the generation, phenotype, and function of memory T cell responses using a murine model of dietary iron modulation in the context of influenza infection. Iron deficient mice have decreased systemic iron levels and develop significant anemia. Increased T cell expression of the transferrin receptor (CD71) is seen in iron deficient mice at baseline. During primary influenza infection, iron deficient mice experience increased weight loss and phenotypic evidence of impairments in T cell activation. Following recovery from infection, iron deficient mice generate increased influenza specific memory T cells which exhibit impaired ability to produce IFN{gamma}, most notably within the lung. Importantly, the ability to produce IFN{gamma} and TNF is not recovered by co-culture with iron replete dendritic cells, suggesting a T cell intrinsic alteration in functional memory formation. Altogether, these results isolate a critical effect of nutritional iron deficiency on T cell memory development and function.

immunology↗

bioRxiv2022

Differentiated neuroblastoma cells remain epigenetically poised for de-differentiation to an immature state

Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for a significant share of childhood cancer deaths. Prior studies utilizing RNA sequencing of bulk tumor populations showed two predominant cell states characterized by high and low expression of neuronal genes. Although cells respond to treatment by altering their gene expression, it is unclear whether this reflects shifting balances of distinct subpopulations or plasticity of individual cells. Using neuroblastoma cell lines lacking MYCN amplification, we show that the antigen CD49b distinguishes these subpopulations. CD49b expression marks proliferative cells with an immature gene expression program, while CD49b-negative cells express differentiated neuronal marker genes and are quiescent. Sorted populations spontaneously switch between CD49b expression states in culture, and CD49b-negative cells can generate rapidly growing, CD49b-positive tumors in mice. We profiled H3K27ac to identify enhancers and super enhancers that are specifically active in each population and find that CD49b-negative cells maintain the priming H3K4me1 mark at elements that are active in CD49b-high cells. Improper maintenance of primed enhancer elements thus may underlie cellular plasticity in neuroblastoma, representing potential therapeutic targets for this lethal tumor. Summary StatementThis study demonstrates that neuroblastoma cells can interconvert between a state characterized by expression of neuronal genes and a de-differentiated state.

cancer biology↗