Quorum-Sensing in CD4(+) T Cell Homeostasis: A Hypothesis and a Model

Abstract

Homeostasis of lymphocyte numbers is believed to be due to competition between cellular populations for a common niche of restricted size, defined by the combination of interactions and trophic factors required for cell survival. Here we propose a new mechanism: homeostasis of lymphocyte numbers could also be achieved by the ability of lymphocytes to perceive the density of their own populations. Such a mechanism would be reminiscent of the primordial quorum-sensing systems used by bacteria, in which some bacteria sense the accumulation of bacterial metabolites secreted by other elements of the population, allowing them to "count" the number of cells present and adapt their growth accordingly. We propose that homeostasis of CD4(+) T cell numbers may occur via a quorum-sensing-like mechanism, where IL-2 is produced by activated CD4(+) T cells and sensed by a population of CD4(+) Treg cells that expresses the high-affinity IL-2Rα-chain and can regulate the number of activated IL-2-producing CD4(+) T cells and the total CD4(+) T cell population. In other words, CD4(+) T cell populations can restrain their growth by monitoring the number of activated cells, thus preventing uncontrolled lymphocyte proliferation during immune responses. We hypothesize that malfunction of this quorum-sensing mechanism may lead to uncontrolled T cell activation and autoimmunity. Finally, we present a mathematical model that describes the key role of IL-2 and quorum-sensing mechanisms in CD4(+) T cell homeostasis during an immune response.

Keywords: CD4+ T cells; IL-2; autoimmunity; homeostasis; immune-therapy; mathematical modeling; quorum sensing; regulatory T cells.

Figure 1

(A) Quorum-sensing. The presence of IL-2 and the ability of the Treg cells to detect its levels are crucial to the homeostasis of the immune system. Quorum-sensing in this case is defined as an indirect feedback loop where the IL-2 produced by a subpopulation of activated T cells (among others) is detected (sensed) by a subpopulation of CD4⁺ Treg cells expressing the high-affinity IL-2Rα-chain; these cells contribute to controlling the number of CD4⁺ T cells. In other words, the overall CD4⁺ T cell populations sense the produced quantities of IL-2 and adapt their behavior accordingly. (B) Failure of quorum-sensing by defective sensor molecule. The inability to detect IL-2 because of defects in IL-2R expression (in IL-2Rα^−/− or IL-2Rβ^−/− mice) or signaling (in STAT5^−/− mice) leads to lymphoid hyperplasia and autoimmune disease. (C) Failure of quorum-sensing due to absence of the sensed molecule. In the absence of IL-2, Treg cells do not survive, which causes lymphoid hyperplasia and autoimmune pathology.

Figure 2

Trajectories of the deterministic model for the parameter set given in Table 1, with the following initial conditions: 100 naïve cells (blue) and 10 regulatory cells (red). (A) Data shown over a time course of 2 weeks. The immune response peaks at ∼7 days, then declines to a homeostatic equilibrium dominated by memory cells. (B) Data shown over a time course of 8 weeks. The contraction phase occurs over an extended time period of ∼20 days for memory cells and ∼40 days for regulatory cells.

Figure 3

Realizations of the stochastic model carried out using the Gillespie algorithm. All parameters and initial conditions are the same as in the deterministic model, with (A,B), respectively, correlating to (A,B) from Figure 2. There is a higher degree of noise at equilibrium for memory cells, which is due to memory cells repeatedly receiving antigen-mediated signals to become IL-2-producing, then reverting back to a non-IL-2-producing state.