Cell-density independent increased lymphocyte production and loss rates post-autologous HSCT

Baliu-Piqué, Mariona; Hoeven, Vera van; Drylewicz, Julia; Wagen, Lotte E. van der; Janssen, Anke; Otto, Sigrid A.; Zelm, Menno C. van; Boer, Rob J. de; Kuball, Jürgen; Borghans, José A. M.; Tesselaar, Kiki

doi:10.7554/elife.59775

Cited by 10 publications

(17 citation statements)

References 54 publications

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“…We showed previously that apparent density-dependent effects on naive T cell survival following thymectomy can also be explained by adaptive or selective processes ( den Braber et al, 2012 ; Rane et al, 2018 ). Similarly, in humans, any regulation of a natural set-point appears to be incomplete at best; naive T cell numbers in HIV-infected adults typically do not normalise following antiretroviral therapy ( Hazenberg et al, 2000 ), and recovery from autologous haematopoietic stem cell transplant results in persistent perturbations of T cell dynamics ( Baliu-Piqué et al, 2021 ). Dutilh and de Boer, 2003 showed that explaining the kinetics of decline in TREC frequencies in human naive T cells requires an increase in either cell division or survival with age, as naive T cell numbers decline.…”

Section: Discussionmentioning

confidence: 99%

Towards a unified model of naive T cell dynamics across the lifespan

Rane

Hogan

Lee

et al. 2022

eLife

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Naive CD4 and CD8 T cells are cornerstones of adaptive immunity, but the dynamics of their establishment early in life and how their kinetics change as they mature following release from the thymus are poorly understood. Further, due to the diverse signals implicated in naive T cell survival, it has been a long-held and conceptually attractive view that they are sustained by active homeostatic control as thymic activity wanes. Here we employ multiple experimental systems to identify a unified model of naive CD4 and CD8 T cell population dynamics in mice, across their lifespan. We infer that both subsets divide rarely and progressively increase their survival capacity with cell age. Strikingly, this simple model is able to describe naive CD4 T cell dynamics throughout life. In contrast, we find that newly generated naive CD8 T cells are lost more rapidly during the first 3-4 weeks of life, likely due to increased recruitment into memory. We find no evidence for elevated division rates in neonates, or for feedback regulation of naive T cell numbers at any age. We show how confronting mathematical models with diverse datasets can reveal a quantitative and remarkably simple picture of naive T cell dynamics in mice from birth into old age.

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Section: Discussionmentioning

confidence: 99%

Towards a unified model of naive T cell dynamics across the lifespan

Rane

Hogan

Lee

et al. 2022

eLife

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“…The memory T-cell pool eventually turns younger due to the presence of a young source. This could present a potential explanation for the observation that reconstituted T-cell pools have higher proliferation rates after autologous stem-cell transplantation ( 11 ) as the highly-divided circulating memory T cells were replaced with lowly-divided memory T cells. Moreover, if the acquisition of different memory T-cell phenotypes were correlated with the division history of a cell ( 73 ), cellular aging would have exciting implications.…”

Section: Discussionmentioning

confidence: 99%

“…Homeostasis need not be perfect, as in both mice and humans, depleted T-cell pools do not always recover to normal levels ( 9 , 10 ). Notably, after autologous stem-cell transplantation, even patients with reconstituted T-cell pools experienced significantly increased T-cell proliferation and loss rates when compared to healthy age-matched controls ( 11 ). These studies highlight our incomplete understanding of the homeostatic process.…”

Section: Introductionmentioning

confidence: 99%

Effect of cellular aging on memory T-cell homeostasis

2022

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The fact that T-cell numbers remain relatively stable throughout life, and that T-cell proliferation rates increase during lymphopenia, has led to the consensus that T-cell numbers are regulated in a density-dependent manner. Competition for resources among memory T cells has been proposed to underlie this ‘homeostatic’ regulation. We first review how two classic models of resource competition affect the T-cell receptor (TCR) diversity of the memory T-cell pool. First, ‘global’ competition for cytokines leads to a skewed repertoire that tends to be dominated by the very first immune response. Second, additional ‘cognate’ competition for specific antigens results in a very diverse and stable memory T-cell pool, allowing every antigen to be remembered, which we therefore define as the ‘gold-standard’. Because there is limited evidence that memory T cells of the same specificity compete more strongly with each other than with memory T cells of different specificities, i.e., for ‘cognate’ competition, we investigate whether cellular aging could account for a similar level of TCR diversity. We define cellular aging as a declining cellular fitness due to reduced proliferation. We find that the gradual erosion of previous T-cell memories due to cellular aging allows for better establishment of novel memories and for a much higher level of TCR diversity compared to global competition. A small continual source (either from stem-cell-like memory T-cells or from naive T-cells due to repeated antigen exposure) improves the diversity of the memory T-cell pool, but remarkably, only in the cellular aging model. We further show that the presence of a source keeps the inflation of chronic memory responses in check by maintaining the immune memories to non-chronic antigens. We conclude that cellular aging along with a small source provides a novel and immunologically realistic mechanism to achieve and maintain the ‘gold-standard’ level of TCR diversity in the memory T-cell pool.

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“…Nevertheless we speculate that the idea of naive T cell homeostasis in the sense of compensatory or quorum sensing behaviour may well be just a theoretical concept in both mice and humans, at least close to healthy conditions. Indeed recently it has been shown that recovery from autologous haematopoietic stem cell transplant results in persistent perturbations of T cell dynamics 39 , arguing against the idea of a naturally regulated set-point. Perhaps a better model is one in which the thymus drives the generation of the bulk of the T cell pool in the early life and thereafter naive T cell repertoires ‘coast’ out into old age in a cell-autonomous manner.…”

Section: Discussionmentioning

confidence: 99%

“…We showed previously that apparent density-dependent effects on naive T cell survival following thymectomy can also be explained by adaptive or selective processes 2,22 . Similarly, in humans, any regulation of a natural set-point appears to be incomplete at best; naive T cell numbers in HIV-infected adults typically do not normalise following antiretroviral therapy 45 , and recovery from autologous haematopoietic stem cell transplant results in persistent perturbations of T cell dynamics 46 . Dutilh et al 47 showed that explaining the kinetics of decline in TREC frequencies in human naive T cells requires an increase in either cell division or survival with age, as naive T cell numbers decline.…”

Section: Discussionmentioning

confidence: 99%

Towards a unified model of naive T cell dynamics across the lifespan

Rane

Hogan

Lee

et al. 2022

Preprint

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Naive CD4 and CD8 T cells are part of the foundation of adaptive immune responses, but multiple aspects of their behaviour remain elusive. Newly generated T cells continue to develop after they leave the thymus and their dynamics and 'rules of entry' into the mature naive population are challenging to define. The extents to which naive T cells' capacities to survive or self-renew change as they age are also unclear. Further, much of what we know about their behaviour derives from studies in adults, both mouse and human. We know much less about naive T cell dynamics early in life, during which the thymus is highly active and peripheral T cell populations are rapidly established. For example, it has been suggested that neonatal mice are lymphopenic; if so, does this environment impact the behaviour of the earliest thymic emigrants, for example through altered rates of division and loss? In this study we integrate data from multiple experimental systems to construct models of naive CD4 and CD8 T cell population dynamics across the entire mouse lifespan. We infer that both subsets progressively increase their capacity to persist through survival mechanisms rather than through self-renewal, and find that this very simple model of adaptation describes the population dynamics of naive CD4 T cells from birth into old age. In addition, we find that newly generated naive CD8 T cells are lost at an elevated rate for the first 3-4 weeks of life, which may derive from transiently increased recruitment into conventional and virtual memory populations. We find no evidence for elevated rates of division of naive CD4 or CD8 T cells early in life and indeed estimate that these cells divide extremely rarely. Markers of proliferation within peripheral naive T cells are instead inherited from division during thymic development. We also find no evidence for feedback regulation of rates of division or loss of naive T cells at any age in healthy mice, challenging the dogma that their numbers are homeostatically regulated. Our analyses show how confronting an array of mechanistic mathematical models with diverse datasets can move us closer to a complete, and remarkably simple, picture of naive CD4 and CD8 T cell dynamics in mice.

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Cell-density independent increased lymphocyte production and loss rates post-autologous HSCT

Cited by 10 publications

References 54 publications

Towards a unified model of naive T cell dynamics across the lifespan

Towards a unified model of naive T cell dynamics across the lifespan

Effect of cellular aging on memory T-cell homeostasis

Towards a unified model of naive T cell dynamics across the lifespan

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