Why the immune system takes its chances with randomness

Hodgkin, Philip D.; Dowling, Mark R.; Duffy, Ken R.

doi:10.1038/nri3734-c1

Cited by 16 publications

(15 citation statements)

References 15 publications

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“…Likewise, lineage-tracing experiments in vivo have suggested that a single naïve lymphocyte invariably yields a diverse set of progeny [reviewed in (Reiner and Adams, 2014)]. The present results suggest that sequential asymmetric divisions might provide a matrix for clonal descendants to adopt different fates, and this would not be incompatible with the proposition that stochastic elements are also involved (Hodgkin et al, 2014). …”

Section: Discussionsupporting

confidence: 47%

Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation

et al. 2015

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SUMMARY Metazoan sibling cells often diverge in activity and identity, suggesting links between growth signals and cell fate. We show that unequal transduction of nutrient-sensitive PI3K/AKT/mTOR signaling during cell division bifurcates transcriptional networks and fates of kindred cells. A sibling B lymphocyte with stronger signaling, indexed by FoxO1 inactivation and IRF4 induction, undergoes PI3K-driven Pax5 repression and plasma cell determination, while its sibling with weaker PI3K activity renews a memory or germinal center B cell fate. PI3K-driven effector T cell determination silences TCF1 in one sibling cell, while its PI3K-attenuated sibling self-renews in tandem. Prior to bifurcations achieving irreversible plasma or effector cell fate determination, asymmetric signaling during initial divisions specifies a more proliferative, differentiation-prone lymphocyte in tandem with a more quiescent memory cell sibling. By triggering cell division but transmitting unequal intensity between sibling cells, nutrient-sensitive signaling may be a frequent arbiter of cell fate bifurcations during development and repair.

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Section: Discussionsupporting

confidence: 47%

Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation

et al. 2015

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“…Heterogeneity within and between clones of expanding lymphocytes is becoming established as an important characteristic of natural immune responses. Yet, the mechanisms that lead to observed variability, the respective roles of stochastic and deterministic processes, and the functional implications of the resulting heterogeneity are still controversial 17 , 18 . We reason that the disparity between the heterogeneous and stochastic responses of individual cells and the robust responses of cell populations can be reconciled through experimental studies of the dynamic responses of single cells followed under controlled conditions, combined with mathematical modeling.…”

Section: Discussionmentioning

confidence: 99%

“…A number of mechanisms have been suggested to contribute to heterogeneity in T‐cell diversification, including strength of TCR signaling, 10 intrinsic stochastic variability between cells, 17 extrinsic instruction by environmental signaling 18 and asymmetric cell division 12 , 19 , 20 , 21 . Interestingly, it has been shown that heterogeneity in clone size and phenotype occurs also in ex vivo cultures of primary lymphocytes, 13 , 22 , 23 even when cells are stimulated in the absence of antigen‐presenting cells.…”

Section: Clonal Expansion: a Heterogeneous Processmentioning

confidence: 99%

Clonal expansion under the microscope: studying lymphocyte activation and differentiation using live‐cell imaging

Polonsky

Chain²,

Friedman

2015

Immunol Cell Biol

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Clonal expansion of lymphocytes is a hallmark of vertebrate adaptive immunity. A small number of precursor cells that recognize a specific antigen proliferate into expanded clones, differentiate and acquire various effector and memory phenotypes which promote effective immune responses. Recent studies establish a large degree of heterogeneity in the level of expansion and in cell state between and within expanding clones. Studying these processes in vivo, while providing insightful information on the level of heterogeneity, is challenging due to the complex microenvironment and the inability to continuously track individual cells over extended periods of time. Live cell imaging of ex vivo cultures within micro fabricated arrays provides an attractive methodology for studying clonal expansion. These experiments facilitate continuous acquisition of a large number of parameters on cell number, proliferation, death and differentiation state, with single cell resolution on thousands of expanding clones that grow within controlled environments. Such data can reveal stochastic and instructive mechanisms that contribute to observed heterogeneity and elucidate the sequential order of differentiation events.Intercellular interactions can also be studied within these arrays by following responses of a controlled number of interacting cells, all trapped within the same microwell. Here, we describe implementations of live cell imaging within microwell arrays for studies of lymphocyte clonal expansion, portray insights already gained from these experiments, and outline directions for future research. These tools, together with in vivo experiments tracking single cell responses, will expand our understanding of adaptive immunity and the ways by which it can be manipulated.2 Introduction:

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“…Identifying strong clonal concordance would indicate that DD is a lineage primed, inherited property. In contrast, clonal discordance in DD fate, in which cells stop over multiple generations, could result from deterministic programming through an asymmetric cell division1415 or by stochastic regulation1617. Published data cannot distinguish between these possibilities.…”

mentioning

confidence: 99%

T-cell stimuli independently sum to regulate an inherited clonal division fate

et al. 2016

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In the presence of antigen and costimulation, T cells undergo a characteristic response of expansion, cessation and contraction. Previous studies have revealed that population-level reproducibility is a consequence of multiple clones exhibiting considerable disparity in burst size, highlighting the requirement for single-cell information in understanding T-cell fate regulation. Here we show that individual T-cell clones resulting from controlled stimulation in vitro are strongly lineage imprinted with highly correlated expansion fates. Progeny from clonal families cease dividing in the same or adjacent generations, with inter-clonal variation producing burst-size diversity. The effects of costimulatory signals on individual clones sum together with stochastic independence; therefore, the net effect across multiple clones produces consistent, but heterogeneous population responses. These data demonstrate that substantial clonal heterogeneity arises through differences in experience of clonal progenitors, either through stochastic antigen interaction or by differences in initial receptor sensitivities.

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Why the immune system takes its chances with randomness

Cited by 16 publications

References 15 publications

Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation

Asymmetric PI3K Signaling Driving Developmental and Regenerative Cell Fate Bifurcation

Clonal expansion under the microscope: studying lymphocyte activation and differentiation using live‐cell imaging

T-cell stimuli independently sum to regulate an inherited clonal division fate

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