“A simple mechanism, previously known from bacteria, ensures that the immune system strikes a balance between the rapid expansion of immune cells and the prevention of an excessive self-damaging reaction after an infection. This has now been deciphered by scientists at the University Hospital of Freiburg (Germany) and colleagues from the Netherlands and Great Britain. An infection quickly activates T-cells, which leads to their proliferation. The research team has now shown that these cells are able to perceive each other and – based on their density – jointly determine whether or not they should continue to proliferate. The newly discovered mechanism could also help to improve cancer immunotherapies. The study was published in the scientific journal Immunity on 11 February 2020.” (from the Freiburg University Medical Center press release.)
Zenke, S., Palm, M., Braun, J., Gavilov, A., Meiser, P., Böttcher, J., Beyersdorf, N., Ehl, S., Gerard, A., Lämmermann, T., Schumacher, T., Beltman, J., & Rohr, J. (2020). Quorum regulation via nested antagonistic feedback circuits mediated by the receptors CD28 and CTLA-4 confers robustness to T cell population dynamics. Immunity. Published online 11 February 2020. DOI: https://doi.org/10.1016/j.immuni.2020.01.018
T cell clusters are communication hubs for coordination of population dynamics
T cells can regulate their own population dynamics akin to quorum regulation
T cell quorum regulation incorporates two nested antagonistic feedback circuits
- Loop dominance of feedback circuits is controlled by local T cell density
T cell responses upon infection display a remarkably reproducible pattern of expansion, contraction, and memory formation. If the robustness of this pattern builds entirely on signals derived from other cell types or if activated T cells themselves contribute to the orchestration of these population dynamics—akin to bacterial quorum regulation—is unclear. Here, we examined this question using time-lapse microscopy, genetic perturbation, bioinformatic predictions, and mathematical modeling. We found that ICAM-1-mediated cell clustering enabled CD8 + T cells to collectively regulate the balance between proliferation and apoptosis. Mechanistically, T cell expressed CD80 and CD86 interacted with the receptors CD28 and CTLA-4 on neighboring T cells; these interactions fed two nested antagonistic feedback circuits that regulated interleukin 2 production in a manner dependent on T cell density as confirmed by in vivo modulation of this network. Thus, CD8 + T cell-population-intrinsic mechanisms regulate cellular behavior, thereby promoting robustness of population dynamics.