Adaptive Immunity: Maintaining naivety of T cells

Mathematical models encoding biological hypotheses reveal new insight into the dynamics of naive immune cells in mice from birth to old age.
  1. Ken Duffy  Is a corresponding author
  1. Hamilton Institute, Maynooth University, Ireland

Adaptive immunity develops with exposure to pathogens. Unlike the innate immune system, which supplies a fast, general response against threats, the adaptive immune system can recognise and remember specific pathogens, thus providing a long-lasting protection against infections. Its key components, B and T cells, can specifically target the germs causing an infection. However, before these cells can attack specific pathogens, they need to encounter a molecule, known as an antigen, which they recognise and respond to. Until then, these cells are ‘naive’.

Naive T cells are produced in the thymus, an organ that shrinks with age. As the thymus becomes smaller, the number of newly produced naive T cells declines rapidly; however, the body is somehow able to maintain a source of naive T cells throughout its life. So far, it has been unclear how the body does this. A population of cells that has no external source of new cells and is subject to death can be sustained by two intrinsic processes: the remaining cells can adjust their division rates to replace lost cells; or they can die less frequently by extending their lifespan.

As with many areas in biology, studying the immune system is challenging, due to its inherent complexity. Immune cells are motile and can be found in many organs. Moreover, an acute adaptive immune response mobilises many cellular actors, and their offspring can still be active for extended periods following infection. Experimental set ups often lack the ability to monitor all of these factors continuously. Now, in eLife, Sanket Rane (Columbia University), Thea Hogan (University College London; UCL), Edward Lee (Yale University), Benedict Seddon (UCL) and Andrew Yates (Columbia) report on mathematical models that can bridge the gap (Rane et al., 2022).

To question how naive T cell populations in mice are maintained throughout life, and how host age, cell age and cell numbers influence both the proliferation and decrease of naive T cells, the researchers developed mathematical models of the number of cells and their different types. Data from various experimental systems were analysed and several competing hypotheses evaluated.

T cells can be divided into two varieties that can be distinguished by the type of transmembrane glycoprotein they express: CD4+T cells increase the activity of other immune cells by releasing cytokines, while cytotoxic CD8+T cells are involved in killing infected cells and their pathogens. The models revealed that both types of cell appear to be able to regulate their lifespan independently from external factors, dividing rarely in adult mice, and living longer as the mice get older. The model accurately predicted the population dynamics of CD4+T cells in both young and adult mice. However, CD8+T cells appear to have distinct dynamics in newborn mice up to three weeks of age, which seem to lose CD8+T cells at a higher rates than adult mice. These results support a traditional understanding in which the thymus drives the maintenance of a naive T cell pool early on, while later in life, cells regulate their survival rates independently.

As with all scientific studies, there are some caveats that highlight the need for further investigation. First, even if data appear to be consistent with a hypothesis, it does not mean that the hypothesis is true – merely that there is insufficient evidence to reject it. As new data become available, accepted hypotheses should be re-challenged. However, one of the advantages of the statistical approach taken by Rane et al. is that additional predictions from the mathematical models can be readily made, facilitating any further re-examination in light of new data.

Second, the data used throughout the analyses were obtained from laboratory mice living in a sterile environment. In the wild, however, mice are exposed to a wide range of naturally occurring infections. The response to these pathogens results in a far more mature immune system with a substantial immune memory, which may have implications for naive populations (Willyard, 2018; Rosshart et al., 2019).

Lastly, it remains to be seen if the findings obtained from studies in mice also apply to humans. This is particularly relevant here, as evidence suggests that the maintenance of naive T cells may differ fundamentally between the two species (den Braber et al., 2012). Regardless, the scientific method used by Rane et al. is certain to make a significant contribution towards a better understanding of human cell dynamics.


Article and author information

Author details

  1. Ken Duffy

    Ken Duffy is in the Hamilton Institute, Maynooth University, Maynooth, Ireland

    For correspondence
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5587-9356

Publication history

  1. Version of Record published: August 3, 2022 (version 1)


© 2022, Duffy

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


  • 392
    Page views
  • 81
  • 0

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Ken Duffy
Adaptive Immunity: Maintaining naivety of T cells
eLife 11:e81077.
  1. Further reading

Further reading

    1. Computational and Systems Biology
    2. Genetics and Genomics
    Karthickeyan Chella Krishnan, Elie-Julien El Hachem ... Aldons J Lusis
    Research Article

    Mitochondria play an important role in both normal heart function and disease etiology. We report analysis of common genetic variations contributing to mitochondrial and heart functions using an integrative proteomics approach in a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). We performed a whole heart proteome study in the HMDP (72 strains, n=2-3 mice) and retrieved 848 mitochondrial proteins (quantified in ≥50 strains). High-resolution association mapping on their relative abundance levels revealed three trans-acting genetic loci on chromosomes (chr) 7, 13 and 17 that regulate distinct classes of mitochondrial proteins as well as cardiac hypertrophy. DAVID enrichment analyses of genes regulated by each of the loci revealed that the chr13 locus was highly enriched for complex-I proteins (24 proteins, P=2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, P=3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, P=6.9E-05). Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively, and both experimental and statistical analyses supported their causal roles. Furthermore, a large cohort of Diversity Outbred mice was used to corroborate Lrpprc gene as a driver of mitochondrial DNA (mtDNA)-encoded gene regulation, and to show that the chr17 locus is specific to heart. Variations in all three loci were associated with heart mass in at least one of two independent heart stress models, namely, isoproterenol-induced heart failure and diet-induced obesity. These findings suggest that common variations in certain mitochondrial proteins can act in trans to influence tissue-specific mitochondrial functions and contribute to heart hypertrophy, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations.

    1. Computational and Systems Biology
    Swann Floc'hlay, Ramya Balaji ... Stein Aerts
    Research Article Updated

    Wound response programs are often activated during neoplastic growth in tumors. In both wound repair and tumor growth, cells respond to acute stress and balance the activation of multiple programs, including apoptosis, proliferation, and cell migration. Central to those responses are the activation of the JNK/MAPK and JAK/STAT signaling pathways. Yet, to what extent these signaling cascades interact at the cis-regulatory level and how they orchestrate different regulatory and phenotypic responses is still unclear. Here, we aim to characterize the regulatory states that emerge and cooperate in the wound response, using the Drosophila melanogaster wing disc as a model system, and compare these with cancer cell states induced by rasV12scrib-/- in the eye disc. We used single-cell multiome profiling to derive enhancer gene regulatory networks (eGRNs) by integrating chromatin accessibility and gene expression signals. We identify a ‘proliferative’ eGRN, active in the majority of wounded cells and controlled by AP-1 and STAT. In a smaller, but distinct population of wound cells, a ‘senescent’ eGRN is activated and driven by C/EBP-like transcription factors (Irbp18, Xrp1, Slow border, and Vrille) and Scalloped. These two eGRN signatures are found to be active in tumor cells at both gene expression and chromatin accessibility levels. Our single-cell multiome and eGRNs resource offers an in-depth characterization of the senescence markers, together with a new perspective on the shared gene regulatory programs acting during wound response and oncogenesis.