A Major Role for Bim in Regulatory T Cell Homeostasis

Abstract

We have previously shown that regulatory T cells (Treg) accumulate dramatically in aged animals and negatively impact the ability to control persistent infection. However, the mechanism(s) underlying the age-dependent accrual of Treg remain unclear. Here, we show that Treg accumulation with age is progressive and likely not the result of increased thymic output, increased peripheral proliferation, nor from enhanced peripheral conversion. Instead, we found that Treg from aged mice are more resistant to apoptosis than Treg from young mice. Although Treg from aged mice had increased expression of functional IL-7Rα, we found that IL-7R-signaling was not required for maintenance of Treg in vivo. Notably, aged Treg exhibit decreased expression of the pro-apoptotic molecule Bim compared to Treg from young mice. Further, in the absence of Bim, Treg accumulate rapidly, accounting for more than 25% of the CD4+ T cell compartment by 6 months of age. In addition, accumulation of Treg in Bim-deficient mice occurred after the cells left the transitional recent thymic emigrant compartment. Mechanistically, we show that IL-2 drives preferential proliferation and accumulation of Bimlo Treg. Combined, our data suggest that chronic stimulation by IL-2 leads to preferential expansion of Treg having low expression of Bim, which favors their survival and accumulation in aged hosts.

Exacerbation of spontaneous autoimmune nephritis following regulatory T cell depletion in B cell lymphoma 2-interacting mediator knock-out mice

“…Bim -/-mice provide a model of enhanced susceptibility to autoimmune disease due to the failure to delete effector T cells in the thymus. Additionally, Bim -/-mice have enhanced T reg numbers with time due to a protection from apoptosis of T regs with Bim deficiency [26,[37][38][39]. This study showed that Bim -/-mice maintained normal kidney function and normal kidney histology at 2 months of age, but gradually developed chronic kidney disease with significantly heavier proteinuria and higher serum creatinine.…”

“…T regs accumulate in aged animals and, with low expression of Bim, impact negatively the ability to control persistent infection [37,38,46]. In addition, T regs proliferate under IL-2 stimulation through elevation of anti-apoptotic regulators and inhibition of pro-apoptotic Bim [47][48][49].…”

AGE-DEPENDENT CHANGES OF T-REGULATORY AND Th17 SUBSET LEVELS IN PERIPHERAL BLOOD FROM HEALTHY HUMANS

“…Логично было бы предположить, что сразу после рождения субпопуляция Treg представлена в ос-новном тимическими Treg, а в старости, напро-тив -iTreg. Тем не менее на мышах было показа-но, что у старых животных, напротив, отмечается повышение nTreg и снижение уровня iTreg [10]. К сожалению, мнение о том, что мыши являются хорошей моделью для изучения возрастных из-менений в иммунной системе, не подтвердилось.…”

Impact of environmental factors on alloimmunity and transplant fate

“…(81). T cells from hyperlipidemic mice expressed significantly lower levels of the proapoptotic molecule Bim, which has previously been implicated in Treg function, compared with normal mice (82). Changes in Tregs in hyperlipidemic mice also affected tolerance induction based on approaches that require Tregs, such as costimulatory molecule blockade.…”