T Cells Function as A Team to Fight Infection

When faced with an infection, T cells normally follow a remarkably reproducible response pattern of expansion, contraction, and memory formation. Population-intrinsic and -extrinsic regulation of T cells occur, but are not mutually exclusive.

Conventional T cell response is often measured by extrinsic signals, such as those sent by regulatory T cells or dendritic cells, which can be variable and thus difficult to use to infer population size. Alternatively, if a population of T cells mutually controls each other, then the strength of regulatory signals scales with population size in an intrinsic manner.

An international team of scientists collaborating with Albert-Ludwigs University (Freiburg im Breisgau, Germany) used time-lapse microscopy, genetic perturbation, bioinformatic predictions, and mathematical modeling to investigate if CD8+ T cells use quorum regulation to control their population dynamics. The scientists found that activated T cells mutually promote their expansions when they are present at low densities, but they also limit further proliferation once sufficient numbers have been reached. This mechanism leads to efficient amplification of initial immune reactions and also prevents potentially dangerous immunopathologies.

Specifically, CD28 and interleukin-2 (IL-2) induced CD80 expression by activated T cells, which could in turn bind to CD28 to augment IL-2 production. This positive feedback loop perpetuated T-cell expansion. However, at some point it becomes necessary to limit this amplification. This is accomplished through a negative feedback circuit acting via cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), by blocking ligand binding of CD28 and IL-2. This evidence supports a mechanistic explanation of how T-cell population dynamics are regulated in a cell density manner by receiving signals from a variety of cell types.

The team found that Intercellular Adhesion Molecule 1 (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 IL-2 production in a manner dependent on T cell density as confirmed by in vivo modulation of this network. Accordingly, CD8 + T cell-population-intrinsic mechanisms regulate cellular behavior, thereby promoting robustness of population dynamics.

Jan Rohr, MD, the senior author of the study, said, “We showed that these immune cells perceive and regulate each other. The immune cells act as a team and not as autonomously acting individualists. This principle of density control of immune cells is simple and very effective. This makes it reliable and at the same time hopefully accessible for therapeutic approaches.” The study was published on February 11, 2020 in the journal Immunity.

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