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The immune system can be defined as a collection of defense mechanisms, involving complex interactions between different cell populations, working together to protect the integrity of the organism. Its homeostasis is achieved by regulatory mechanisms aiming to keep a constant number of cells. 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 they 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 mechanism, where IL-2 production by activated CD4+ T cells is monitored by a sub-population of CD4+ Treg cells, expressing the high-affinity IL-2Rα- chain, which reciprocally restrains the growth of activated IL-2-producing (IL-2p) CD4+ T cells. In order to explore the proposed quorum-sensing mechanism we investigated the regulation of the size of IL-2-p CD4+ T cells using different IL-2-reporter mice. We found that in the absence of either IL-2 or Treg cells the number of IL-2p cells increases. Administration of IL-2 decreases the number of cells of the IL-2p cellular subset and pertinently, abrogates their ability to produce IL-2 upon in vivo cognate stimulation, while boosting Treg cell numbers. These experimental findings support the presence of a quorum-sensing mechanism, orchestrated by IL-2 and Treg cells, crucial for the maintenance of CD4+ T cells homeostasis. Additionally, the quorum-sensing hypothesis embodies a feedback mechanism to control T cell activation while allowing immune responses to occur, since it likely plays a part in the contraction phase of CD4+ T cell responses. Some preliminary experimental findings emphasizing the quorum-sensing hypothesis in the context of the regulation of immune responses are compiled. A mathematical model describing the role of IL-2 and quorum-sensing mechanism in CD4+ T cell homeostasis during an immune response is presented.
We also hypothesize that malfunction of this quorum-sensing mechanism – by the inability of CD4+ T cells to detect IL-2 due to defects of IL-2R expression, IL-2 signaling or IL-2 production – may lead to uncontrolled T cell activation, lymphoid hyperplasia and lethal autoimmunity scenario.
In conclusion, the quorum-sensing model provides new mechanistic insights impacting in our understanding of autoimmune diseases and will create a new way of thinking about the homeostasis of lymphocyte populations.