Assistant Professor Case Western Reserve University/Northeast Ohio VA Cleveland, Ohio, United States
Introduction/Rationale: Levels of the inflammatory cytokine IL-1b are elevated during aging and are associated with a number of morbidities including autoinflammatory diseases, cardiovascular disease, neurodegenerative diseases, pulmonary disease, type 2 diabetes, and rheumatoid arthritis. Our previous studies of human peripheral blood mononuclear cells (PBMCs) demonstrated that innate cytokines (IL-1b and IL-6) could down-regulate expression of CD127 on T cells and induce proliferation of memory CD4 T cells in vitro, without upregulating the survival factor Bcl2. Here, we revisited these studies to better understand the mechanism(s) of how chronic innate cytokines, like IL-1b, interfere with CD4+ T cell homeostasis.
Methods: PBMCs or purified T cells from healthy human participants were incubated with recombinant human IL-1b, IL-2, or IL-7, as well as blocking reagents targeting these signaling pathways. After 7-9 days, cellular subsets and proliferation were assessed by flow cytometry.
Results: Confirming our previous studies, we found that proliferation of CD4+ T cells in response to IL-1b stimulation of PBMCs differs from that induced by the homeostatic cytokine IL-7 in that IL-1b induces a small polyclonal population of primarily CD4+ memory T cells to rapidly proliferate. While IL-7 stimulation could induce proliferation of purified T cells, IL-1b stimulation could not, demonstrating that an additional PBMC-derived soluble factor is required. Inhibition of IL-2 in PBMC cultures decreased IL-1b stimulation-induced proliferation, suggesting that IL-2 generated during the culture partially contributes to the IL-1b-induced bystander proliferation of memory CD4+ T cells.
Conclusion: Our results provide a novel mechanism of how persistent innate cytokines such as IL-1b can disrupt T cell homeostasis during aging and chronic infections.
