Early emergence of T central memory precursors programs clonal dominance during chronic viral infection

Grassmann, Simon; Mihatsch, Lorenz; Mir, Jonas; Kazeroonian, Atefeh; Rahimi, Roza; Flommersfeld, Sophie; Schober, Kilian; Hensel, Inge; Leube, Justin; Pachmayr, Ludwig O.; Kretschmer, Lorenz; Zhang, Qin; Jolly, Adrien; Chaudhry, M. Zeeshan; Schiemann, Matthias; Čičin‐Šain, Luka; Höfer, Thomas; Busch, Dirk H.; Floßdorf, Michael; Buchholz, Veit R.

doi:10.1038/s41590-020-00807-y

Cited by 40 publications

(35 citation statements)

References 57 publications

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“…This framework is further supported by direct measurements of division speed in vivo, showing that, already by day four after vaccination, CD62L + CMPs undergo on average one division less per day than their CD62Lcounterparts (8). Moreover, recent work confirmed the largely unidirectional differentiation of CMPs into non-CMPs during the expansion phase of a T cell response (9) and the role of CMPs as the major source of long-lasting CD8 + T cell memory (10)(11)(12). However, certain features of our originally proposed stochastic framework are at odds with observations made during the very early phase of T cell activation: First, directly after activation in vivo, CD8 + T cells have been found to divide particularly fast (13,14), conflicting with the idea of an initial emergence of slowly-dividing CMPs.…”

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confidence: 68%

Section: Introductionmentioning

confidence: 79%

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Heritable changes in division speed accompany the diversification of single T cell fate

Plambeck¹,

Kazeroonian²,

Loeffler

et al. 2021

Preprint

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Rapid clonal expansion of antigen specific T cells is a fundamental feature of adaptive immune responses. It enables the outgrowth of an individual T cell into thousands of clonal descendants that diversify into short-lived effectors and long-lived memory cells. Clonal expansion is thought to be programmed upon priming of a single naive T cell and then executed by homogenously fast divisions of all of its descendants. However, the actual speed of cell divisions in such an emerging "T cell family" has never been measured with single-cell resolution. Here, we utilize continuous live-cell imaging in vitro to track the division speed and genealogical connections of all descendants derived from a single naive CD8+ T cell throughout up to ten divisions of activation-induced proliferation. This comprehensive mapping of T cell family trees identifies a short burst phase, in which division speed is homogenously fast and maintained independent of external cytokine availability or continued T cell receptor stimulation. Thereafter, however, division speed diversifies and model-based computational analysis using a novel Bayesian inference framework for tree-structured data reveals a segregation into heritably fast and slow dividing branches. This diversification of division speed is preceded already during the burst phase by variable expression of the interleukin-2 receptor alpha chain. Later it is accompanied by selective re-expression of memory marker CD62L in slower dividing branches. Taken together, these data demonstrate that T cell clonal expansion is structured into subsequent burst and diversification phases the latter of which coincides with specification of memory vs. effector fate.

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mentioning

confidence: 68%

Section: Introductionmentioning

confidence: 79%

Heritable changes in division speed accompany the diversification of single T cell fate

Plambeck¹,

Kazeroonian²,

Loeffler

et al. 2021

Preprint

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“…We reasoned that single-cell fate mapping should allow us to discriminate between these two modes of differentiation. As described previously (Grassmann et al, 2019(Grassmann et al, , 2020, we used retrogenic color barcoding to track single-cell-derived NK cell responses against MCMV. We transduced hematopoietic stem cells (HSCs) with retroviral constructs encoding various fluorescent proteins and generated retrogenic mice by transplanting these HSCs into irradiated hosts (Figure S1B).…”

Section: Individual Ly49h + Nk Cells Follow Two Distinct Paths Of Differentiation Upon MCMV Infectionmentioning

confidence: 99%

Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection

et al. 2021

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Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection Graphical abstract Highlights d Adaptive-like NK cell responses to MCMV encompass conventional and ILC1-like lineages d ILC1-like NK cells show enhanced cytokine production and splenic residency d ILC1-like NK cells show EOMES expression, target-specific cytotoxicity, and clonal expansion d ILC1-like NK cells drive cDC1 clustering and CD8 + T cell priming dependent on Ly49H and Batf3

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“…Instead, our data suggest that the explanation for the size differences between MCMV-specific CD8 + T-cell responses and for memory inflation in general should be sought earlier during infection. In line with this, it has recently been shown that the inflationary potential of CMV-specific T-cells is set early, during the acute phase of the response, and is reflected by their early transcriptomic profile (28).…”

Section: Discussionmentioning

confidence: 68%

Turnover of MCMV-expanded CD8⁺ T-cells is similar to that of memory phenotype T-cells and independent of the magnitude of the response

Baliu-Piqué

Drylewicz

Zheng

et al. 2021

Preprint

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The potential of memory T-cells to provide protection against re-infection is beyond question. Yet, it remains debated whether long-term T-cell memory is due to long-lived memory cells. There is ample evidence that blood-derived memory phenotype CD8+ T-cells maintain themselves through cell division, rather than through longevity of individual cells. It has recently been proposed, however, that there may be heterogeneity in the lifespans of memory T-cells, depending on factors such as exposure to cognate antigen. Cytomegalovirus (CMV) infection induces not only conventional, contracting T-cell responses, but also inflationary CD8+ T-cell responses, which are maintained at unusually high numbers, and are even thought to continue to expand over time. It has been proposed that such inflating T-cell responses result from the accumulation of relatively long-lived CMV-specific memory CD8+ T-cells. Using in vivo deuterium labelling and mathematical modelling, we found that the average production rates and expected lifespans of mouse CMV-specific CD8+ T-cells are very similar to those of bulk memory-phenotype CD8+ T-cells. Even CMV-specific inflationary CD8+ T-cell responses that differ three-fold in size, were found to turn over at similar rates.

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Early emergence of T central memory precursors programs clonal dominance during chronic viral infection

Cited by 40 publications

References 57 publications

Heritable changes in division speed accompany the diversification of single T cell fate

Heritable changes in division speed accompany the diversification of single T cell fate

Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection

Turnover of MCMV-expanded CD8⁺ T-cells is similar to that of memory phenotype T-cells and independent of the magnitude of the response

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Early emergence of T central memory precursors programs clonal dominance during chronic viral infection

Cited by 40 publications

References 57 publications

Heritable changes in division speed accompany the diversification of single T cell fate

Heritable changes in division speed accompany the diversification of single T cell fate

Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection

Turnover of MCMV-expanded CD8+ T-cells is similar to that of memory phenotype T-cells and independent of the magnitude of the response

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Turnover of MCMV-expanded CD8⁺ T-cells is similar to that of memory phenotype T-cells and independent of the magnitude of the response