Article activity feed

  1. Evaluation Summary:

    This paper is of broad interest to cellular biologists and immunologists. It offers new insights into how T cell compartments are regulated in vivo defining a new perspective on how the T cell compartment is regulated to maintain immune homeostasis and afford long-term immune protection. By assessing data from a range of mouse model systems, the key deduction is that a simple hypothesis, one which notably does not have complex feedback regulation of cell numbers, provides a remarkably good explanation of the data.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

    Was this evaluation helpful?
  2. Reviewer #2 (Public Review):

    This paper questions the processes that lead to T cells being sustained throughout life despite the involution of the thymus with age. As the temporal dynamics of individual cells and their offspring cannot be readily traced in vivo, a combination of new experimentation and reassessment of published data with hypothesis-based mathematical model fitting is used to assess the merits of alternative possibilities.

    The first experimental methodologies used for primary data is a cohort of congenic busulfan chimeric mice who underwent bone marrow transplants between 7 and 25 weeks of age. With distinct CD45 variants on the host and donor cells, measurements at distinct time points reveal relative information on the proportion of original and donor cells.

    The considered interpretation of the first section indicates the general issue that care must be taken when naively fitting mathematical models as the marginally better fitting model to the CD8+ data proves to be inconsistent with data shown elsewhere. The age-dependent loss model, which well explains the CD4+ data and is a good explanation of the CD8+ data, is then further explored.

    The mathematical model is used to make out-of-sample predictions based on a data set published by another lab (Houston et al.PNAS 2011) measuring the ratio of recent thymic emigrants to mature naive cells, through Rag2 GFP+ expression. It is demonstrated that the age-dependent loss model predicted the trends, but not the quantitative values, in both the CD4 and CD8 ratios, while the age-dependent division model does not. Although one would not necessarily expect perfect quantitative alignment across such distinct systems, one notices that the quantitative fit is not perfect. While no suggested explanation is provided by the authors, it's clear why the age-dependent division model is rejected.

    The second of two experimental methodologies is a Rag GFP+ Ki67 RFP+ reporter mouse to enable tracking of recent thymic emigrants in neonates to enable mathematical models to extract quantitative information on kinetics, dependent on model assumptions. For CD4+ cells, the model based on adult mice makes notably accurate predictions.

    To resolve a conundrum in the early time point CD8+ data, externally published data (Reynaldi et al., PNAS 2019) is reexamined. At this stage, the mathematical model becomes more complex and so inferences are a little more speculative, but - within the natural caveats that come with those - the inference would be that naive CD8 T cells rarely divide and increase their capacity to survive with cell age, but to explain the early time point data it is suggested that generated within the first few weeks of life are lost at a higher baseline rate than those in adults.

    The discussion element of the paper recapitulates and contextualises earlier inferences, neatly summarising the findings. The Supplementary Information is extensive and clear and should enable reconstruction of the work by others. While further experimental data may support or challenge the inferences made in the present paper, the clear line of reasoning, sophisticated set of considered data, and analysis tools are convincing and the piece would form a worthy addition to the literature.

    Was this evaluation helpful?
  3. Reviewer #1 (Public Review):

    The paper uses a very clever combination of datasets and mathematical models to distinguish how host age, cell age, and cell numbers influence the proliferation and loss rates of naive T cells in mice throughout their life. The paper demonstrates very nicely how easily one can draw false conclusions based on cross-sectional data on T-cell turnover. For example, the observation that naive T cells in young mice have higher levels of Ki67 expression is generally interpreted as evidence for homeostatic regulation of cell numbers, which are relatively low at a young age. This paper shows that in fact, these high Ki67 levels are more likely unrelated to cell numbers and instead reflect the different dynamics (or even just different inherited Ki67 expression levels) of cells that have recently migrated from the thymus. The analyses show that a basic model in which naive T cells gradually attain extended lifespans in a cell-intrinsic manner provides a good description of the data obtained from clean laboratory mice.

    It remains unclear how these data should be translated to the human situation, as naive T-cell maintenance in mice and humans differ fundamentally. While in mice, the vast majority of new naive T cells are made by the thymus, and naive T cells hardly undergo cell division without differentiation to memory cells, in humans the situation is completely different. Naive T cells in human adults are extremely long-lived and the cells that are being renewed are made by peripheral T-cell division, not by output from the thymus. It, therefore, remains questionable whether the insights obtained in this paper directly translate to the human situation. Related to this, it should be noted that all findings described here were made in clean laboratory mice. It remains unknown to what extent the described mechanisms may differ in a more natural setting in which mice are regularly exposed to foreign antigens.

    Was this evaluation helpful?