About

Norah Smith is a researcher whose work focuses on the development and function of T cells, particularly CD8+ T cells, and their role in immune responses. Her research includes studying age-related differences in recent thymic emigrants, the innate programming of αβ T cells during developmental hematopoiesis, and the regulatory programs of microRNAs in T cell responses. She has contributed to understanding how early microbial exposure shapes adult immunity, the gene regulatory basis of T cell activation, and the mechanisms underlying T cell memory formation and differentiation. Her work also explores the impact of developmental origin on T cell fate decisions during infection, the influence of metabolic pathways such as glycolytic metabolism on T cell memory development, and the molecular signals that promote T cell recruitment to specific tissues like the brain during infections. Additionally, her research investigates the effects of neonatal infections on T cell repertoires, the dynamics of neonatal CD8+ T-cell responses, and the broader principles of immune cell development that shape immune function throughout life.

Research topics

• Biology
• Cell biology
• Genetics
• Immunology
• Chemistry
• Geology

Selected publications

• Single-cell gene expression and TCR profiling reveal age-related differences in recent thymic emigrants

  iScience · 2026-04-02

  articleOpen access

  RTEs and found that they exhibit distinct phenotypes and functions. Paired single-cell transcriptomics and T cell receptor (TCR) sequencing showed that neonatal RTEs exhibit a more effector-like gene expression profile than adult RTEs, and the most pronounced effector-gene bias was found in neonatal RTEs that utilize germline-encoded TCRs. Collectively, these data reveal how the RTE pool changes during development and how TCR usage contributes to phenotypic heterogeneity in the neonatal and adult RTE pools.

  PublisherDOI

• Recent thymic emigrants preferentially undergo memory inflation after persistent infection

  PLoS Pathogens · 2025-07-28

  articleOpen accessCorresponding

  Cytomegalovirus (CMV) leads to a unique phenomenon known as 'memory inflation,' where antigen-specific memory CD8 + T cells continue to accumulate in the peripheral tissues during the latent stage of infection. However, it is still not clear how the inflating pool of memory CD8 + T cells is generated and maintained. In this study, we used murine cytomegalovirus (MCMV) as a model of persistent infection and fate-mapping mice to determine the dynamics of CD8 + T cell recruitment into the memory pool. We found that neonatal exposure to CMV leads to an expansion of newly produced CD8 + T cells called recent thymic emigrants, or RTEs, which are maintained in the long-lived memory compartment. In contrast, CD8 + T cells produced after the acute phase of infection contribute minimally to memory inflation. We also observed notable phenotypic differences between the RTEs and mature CD8 + T cells that were recruited into the memory inflation response. Whereas the RTEs present at the time of infection gave rise to more effector memory cells, the mature CD8 + T cells were biased towards becoming central memory cells. Importantly, the preferential recruitment of RTEs into the effector memory pool also occurs during adult exposure to CMV. Collectively, these data demonstrate that persistent infection expands the RTE population, and timing of infection dictates whether neonatal or adult RTEs are 'locked in' to the memory pool.

  PublisherDOI

• An efficient framework to decipher microRNA regulatory programs applied to T cells

  Genes and Immunity · 2025-08-18

  articleOpen access

  Naïve CD8 + T cells are heterogenous, with subsets exhibiting divergent kinetics and functions post-activation. MicroRNAs, important mediators of post-transcriptional regulation, contribute to specification of different naïve T cell subsets. However, the microRNA regulatory circuits mediating functional specialization of naïve subsets are poorly understood. Here, we profiled microRNA expression in diverse subsets of naïve CD8 + T cells, revealing significant differences in their microRNA expression landscapes. We developed a novel framework, miR-Inf, to decipher microRNA regulatory programs. miR-Inf features two innovative attributes: (i) an efficient approach based on intron-exon ratios to estimate gene decay rates from a compendium of RNA-seq profiles, in order to better capture microRNA regulatory effects, and (ii) identification of cell-type-specific microRNA targets by integrating decay rate data and microRNA expression data. We applied this framework to identify consequential miRNAs in naïve CD8 + T cell subsets and predicted their subset-specific targets. Our analyses revealed that miR-29, a microRNA known to be important in CD8 + T cells, likely functions by modulating transcripts encoding epigenetic factors, thereby pre-programming different naïve T cell subsets to exhibit different immune responses post-activation. Collectively, our data and broadly applicable framework defined microRNA regulatory circuits across a variety of naïve CD8 + T cell subsets.

  PublisherOA PDFDOI

• Developmental hematopoiesis: innate programming of αβ T cells

  Experimental Hematology · 2025-10-30 · 1 citations

  reviewOpen access
  PublisherOA PDFDOI

• Humanizing a CD28 signaling domain affects CD8 activation, exhaustion and stem-like precursors

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-13

  preprintOpen access

  Abstract CD28 ligation provides critical signals that modulate activated T cell fate. In a human to mouse reverse-engineering approach, a single amino acid substitution adjacent to the C-terminal proline-rich domain created CD28 A210P mice with enhanced signaling. CD28 A210P mice experienced pro-inflammatory responses to CD28 superagonist antibody, analogous to severe cytokine storm induced in a human clinical trial, with a striking increase of activated CD8 T cells. In acute and chronic viral infections, early activation and expansion of CD28 A210P CD8 effector T cells increased, with accelerated exhaustion in chronic infection. Mechanistically, CD28 A210P enhanced JunB, IL-2, and inhibitory receptors driven by MEK1/2. Generation of CD28 A210P stem-like progenitor (Tpex) cells was enhanced in acute and chronic infections, and further expanded by PD-L1 blockade in chronically-infected mice. Thus, ‘humanized’ PYAP mice reveal key roles for CD28 signaling strength in CD8 activation, accelerating exhaustion during antigen persistence, while promoting and sustaining Tpex during acute and chronic viral infection. One sentence Summary A single amino acid substitution adjacent to PYAP to ‘humanize’ CD28 signaling enhances superagonist response, early CD8 activation and Tpex generation during viral infection while accelerating exhaustion and sustaining Tpex during chronic infection. Graphical Abstract: ‘Humanized’ CD28 PYAPP enhances numbers of CD8 T cell effectors and stem-like precursors during acute viral infection, and accelerates exhaustion while sustaining increased self-renewing Tpex cells that are favored during PD-L1 blockade.

  PublisherOA PDFDOI

• Single-cell multiomics reveals the distinct properties of neonatal and adult recent thymic emigrants

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-01

  preprintOpen access

  Abstract Following thymic egress, CD8+ T cells must undergo a post-thymic maturation process to transition from a recent thymic emigrant (RTE) to a mature naïve T cell. Since the neonatal T cell pool is comprised of significantly more RTEs, the prevailing notion is that neonatal CD8+ T cells behave differently than their adult counterparts simply because they have undergone less post-thymic maturation. To test this theory, we leveraged a fate mapping mouse model and paired single cell transcriptome and TCR sequencing to compare neonatal and adult CD8+ RTEs that have undergone the same amount of post-thymic maturation. Interestingly, we found that neonatal and adult CD8+ RTEs exhibit distinct phenotypes, gene expression profiles, TCR usage, and functions. These data suggest that neonatal CD8+ T cells are not simply immature adult CD8+ T cells and that age-related changes in CD8+ T cell functions in early life cannot be attributed solely to differences in the amount of post-thymic maturation.

  PublisherOA PDFDOI

• Recent thymic emigrants are preferentially recruited into the memory pool during persistent infection

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-08

  preprintOpen access

  Abstract Cytomegalovirus (CMV) leads to a unique phenomenon known as ‘memory inflation,’ where antigen-specific memory CD8+ T cells continue to accumulate in the peripheral tissues during the latent stage of infection. However, it is still not clear how the inflating pool of memory CD8+ T cells is generated and maintained. In this study, we used murine cytomegalovirus (MCMV) as a model of persistent infection and fate-mapping mice to determine the dynamics of CD8+ T cell recruitment into the memory pool. We found that neonatal exposure to CMV leads to an expansion of newly made CD8+ T cells (recent thymic emigrants, RTEs), which are maintained in the long-lived memory compartment. In contrast, CD8+ T cells made during the latent phase of infection (mature CD8+ T cells) contribute little to the memory pool. We also observed notable phenotypic differences between RTEs and mature cells. Whereas RTEs present at the time of infection gave rise to more effector memory cells, the cells produced later in infection were biased towards becoming central memory cells. Importantly, the preferential recruitment of RTEs into the effector memory pool also occurs during adult exposure to CMV. Collectively, these data demonstrate that persistent infection expands the RTE population, and timing of infection dictates whether neonatal or adult RTEs are ‘locked in’ to the memory pool. Author Summary Following infection with CMV, CD8+ T cells accumulate in the blood and peripheral organs over time, a feature termed ‘memory inflation’. However, it is not clear whether memory inflation is due to the continuous recruitment of cells made during the latent stage of infection or expansion of CD8+ T cells that were present at the time of infection. To address this question, we used a fate-mapping mouse model and examined the recruitment of CD8+ T cells that were produced during different stages of infection. Surprisingly, we discovered that CD8+ T cells exported from the thymus just prior to infection are preferentially recruited and maintained in the memory pool. In contrast, CD8+ T cells made during the latent stage contribute minimally to the inflating pool and exhibit a less differentiated phenotype. These results provide a new conceptual framework for understanding how the memory pool is generated and maintained after persistent viral infection.

  PublisherOA PDFDOI

• Neonatal CD8+ T Cells Resist Exhaustion during Chronic Infection

  The Journal of Immunology · 2024-01-17 · 4 citations

  articleOpen access

  Chronic viral infections, such as HIV and hepatitis C virus, represent a major public health problem. Although it is well understood that neonates and adults respond differently to chronic viral infections, the underlying mechanisms remain unknown. In this study, we transferred neonatal and adult CD8+ T cells into a mouse model of chronic infection (lymphocytic choriomeningitis virus clone 13) and dissected out the key cell-intrinsic differences that alter their ability to protect the host. Interestingly, we found that neonatal CD8+ T cells preferentially became effector cells early in chronic infection compared with adult CD8+ T cells and expressed higher levels of genes associated with cell migration and effector cell differentiation. During the chronic phase of infection, the neonatal cells retained more immune functionality and expressed lower levels of surface markers and genes related to exhaustion. Because the neonatal cells protect from viral replication early in chronic infection, the altered differentiation trajectories of neonatal and adult CD8+ T cells is functionally significant. Together, our work demonstrates how cell-intrinsic differences between neonatal and adult CD8+ T cells influence key cell fate decisions during chronic infection.

  PublisherOA PDFDOI

• Deciphering gene regulatory programs underlying functionally divergent naïve T cell subsets

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-11-07 · 2 citations

  preprintOpen access

  Abstract Naïve CD8+ T cells are a heterogeneous population, with different subsets possessing distinct functions and kinetics upon activation. However, the gene regulatory circuits differentiating these naïve subsets are not well studied. In this work, we analyzed a large collection of public and newly generated RNA-seq and ATAC-seq profiles of different subsets of naïve CD8+ T cells, revealing significant differences in the gene regulatory landscapes between subsets. We leveraged these data by employing a network inference algorithm, Inferelator, to identify the transcriptional regulatory circuits active in each subset. The predicted transcriptional network of the naïve CD8+ T cell pool was validated by multiple orthogonal approaches, including CUT&Tag and Micro-C. Interestingly, our network analysis revealed a novel role for Eomes in promoting effector cell differentiation in specific cell subsets. Moreover, we uncovered multiple novel regulators across a variety of subsets and discovered several modules of genes that were co-regulated by shared sets of transcription factors in distinct subsets. Collectively, our data defines the gene regulatory programs differentiating naïve CD8+ T cells and facilitates the identification of novel transcription factors that may alter the propensity of naïve CD8+ T cells to become effector or memory cells after infection.

  PublisherOA PDFDOI

• Cutting Edge: Retinoic Acid Promotes Brain-homing of CD8+ T Cells during Congenital Cytomegalovirus Infection

  The Journal of Immunology · 2024-08-12 · 4 citations

  articleOpen access

  The most common congenital viral infection is CMV, which leads to numerous neurologic disabilities. Using a mouse model of congenital CMV, we previously determined that Ag-specific CD8+ T cells traffic to the brain in a CCR9-dependent manner. The mechanism by which these CD8+ T cells acquire a CCR9-dependent "brain-tropic" phenotype remains unclear. In this study, we identify the key factor that imprints brain homing specificity on CD8+ T cells, the source of production, and the location where CCR9 expression is induced. Specifically, we discovered that CCR9 is induced on CD8+ T cells by retinoic acid-producing CD8α+ dendritic cells in the cervical lymph node postinfection. We found that retinoic acid is important for CD8+ T cells to establish tissue residency in the brain. Collectively, our data expand the role of retinoic acid during infection and mechanistically demonstrate how CD8+ T cells are primed to protect the brain during congenital viral infection.

  PublisherOA PDFDOI

Recent grants

• Developmental layers in the CD8+ T cell response to infection.

  NIH · $430k · 2019–2021

Frequent coauthors

• Brian D. Rudd

  31 shared

• Andrew Grimson

  Cornell University

  15 shared

• Barbara Baird

  Cornell University

  12 shared

• Jocelyn Wang

  Natera (United States)

  11 shared

• Miles P. Davenport

  UNSW Sydney

  11 shared

• Cybelle Tabilas

  Cornell University

  10 shared

• David Holowka

  Cornell University

  9 shared

• Eric Denkers

  University of New Mexico

  9 shared

Labs

• Rudd labPI