Dissecting the ontogeny of T cell memory by single-cell fate mapping
Pediatric and Adolescent Medicine
Final Report Abstract
Due to their central role in protecting our bodies the underlying mechanisms governing the strikingly dynamic behavior of activated T cells upon infection constitute an intensely studied field. A striking feature of T cells is that their behavior combines two seemingly contradictory features: it is highly adaptable, yet their responses are nevertheless very robust. Our understanding of the regulation of T cell responses has largely focused on mechanisms that are either cell-intrinsic or build on signals provided by other cell types, like dendritic cells or regulatory T cells. While cell-intrinsic heterogeneity can shape the behaviour of T cells, conceptually an entirely cell-intrinsic regulation of T cell behaviour may be difficult to reconcile with the flexibility necessary to adjust T behavior to the requirements of different infections. On the other hand, control of T cells via signals provided by dendritic cells (DCs) and regulatory T (Treg) cells is prone to variability, because tailoring the strength of extrinsic regulatory signals to the size of the population regulated is challenging. Building on the idea that if members of a population mutually control each other, the strength of regulatory signals scales with the population size, the data generated within this project provides a solution to this conundrum. Specifically, our work demonstrates that activated conventional CD8+ T cells are able to mutually control each other in a manner akin to quorum-based regulation observed prokaryotes. Furthermore, we elucidate mechanisms underlying this additional layer of regulation. Specifically, our work showcases that T cell quorum-regulation can affect expansion and contraction of T cells as well as their differentiation. Concepts underlying quorum-regulation have recently gained attention in the field of systems biology due to their impressive ability to strike a balance between the seemingly contradictory fields of of adaptability and robustness. As demonstrated in our work, quorum-regulated systems can achieve this, if their network builds on interlaced antagonistic feedback circuits. Furthermore, we show that T cell quorum regulation does not act in isolation, but is able to integrate signals from other cell types, like dendritic cells. This equips the system with the flexibility required to adjust T behavior to different infections, because the network architecture enables both the amplification of weak extrinsic signals and the attentuation of strong T cell population-extrinsic inputs. Our work has unravelled several novel and very fundamental aspects of T cell mediated immune responses. Specifically, we have successfully adressed the central goal of this project, namely to provide a better understanding into mechanismns underlying the population dynamics and functional diversification of T lymphocytes upon infection. Although being fundamental in nature, the mechanisms delineated can help to improve immunotherapies and vaccination strategies by providing additional levers for modulating T cell behavior.
Publications
- Trends Immunol. 2014 Apr;35(4):170-7. Single cell behavior in T cell differentiation
Rohr JC, Gerlach C, Kok L, Schumacher TN
(See online at https://doi.org/10.1016/j.it.2014.02.006) - Trends Immunol. 2015 Jul;36(7):392-400. Assessing T lymphocyte function and differentiation by genetically encoded reporter systems
Hoekstra ME, Dijkgraaf FE, Schumacher TN, Rohr JC
(See online at https://doi.org/10.1016/j.it.2015.05.008) - BMC Bioinformatics. 2016 Apr 2;17:151. Reproducibility of Illumina platform deep sequencing errors allows accurate determination of DNA barcodes in cells
Beltman JB, Urbanus J, Velds A, van Rooij N, Rohr JC, Naik SH, Schumacher TN
(See online at https://doi.org/10.1186/s12859-016-0999-4) - Immunity. 52, 1–15, February 18, 2020. Quorum-regulation mediated by nested antagonistic feedback circuits via CD28 and CTLA-4 receptors confers robustness to CD8+ T cell population dynamics
Zenke S, Palm MM, Braun J, Gavrilov A, Meiser P, Böttcher JP, Beyersdorf N, Ehl S, Gerard A, Lämmermann T, Schumacher TN, Beltman JB, Rohr JC
(See online at https://doi.org/10.1016/j.immuni.2020.01.018)
