Year: 2014
Type: article
Abstract: Aging is associated with a significant decline in immune function, both in the innate and adaptive immune system.This deterioration in immune function, termed immunosenescence, increases susceptibility to infectious diseases and cancers, and decreases vaccine efficacy in the elderly.Regulatory T cells, a suppressive CD4+ T cell subset, significantly accumulate with age in humans and mice and contribute to immunosenescence.This accrual could be driven by several mechanisms, including increased thymic production, proliferation, conversion from naïve CD4+ T cells, and survival.We reported earlier that only increased ex vivo Treg survival is observed, and this correlated with the loss of pro-apoptotic Bim expression in aging Treg (Appendix 2).Further, germline deletion of Bim promoted a more rapid Treg accrual with age, suggesting that Bim negatively regulates Treg homeostasis (Appendix 2).In this dissertation, we aimed to further understand the mechanisms regulating Treg Bim expression and Treg homeostasis with age.While germline deletion of Bim promotes Treg accrual, it remained unclear whether the effects of Bim are (i) Treg intrinsic and (ii) dominant to other pro-apoptotic molecules.In Chapter 3, we generated FoxP3-Cre Bim f/f mice that have Bim deleted specifically in Treg, and showed that Treg intrinsic loss of Bim is sufficient to drive Treg accrual with age.Further, the loss of the downstream mediators of Bim, Bax and Bak, did not exacerbate Treg accumulation, suggesting Bim is the dominant pro-apoptotic molecule regulating Treg accrual.Decreased Bim expression occurs both at the population level and cellular level because (i) there is a selection for a Treg population that is normally Bim lo and (ii) these cells further decrease Bim expression with age.The ! iii! emergence of CD25 lo Bim lo Treg is partly driven by declining IL-2 levels with age.Additionally, aged Treg are more dependent on IL-15 for maintenance and IL-15 promotes Treg accrual by combating Bim-mediated death.Together, our work in Chapter 3 show that aging favors the accrual of the CD25 lo Bim lo Treg population that is more dependent on IL-15 as IL-2 levels become limiting.In Chapter 4, we show that the Treg that accumulate with age have an "effector" Treg phenotype.Effector Treg have recently been defined as CD4+ FoxP3+ cells that are CD44 hi CD62L lo .In young mice, the effector Treg make up approximately 50% of the Treg pool in secondary lymphoid tissues.However in old mice, nearly all Treg are effector Treg.Aged effector Treg express high levels of ICOS and CD69, and ICOS promotes effector Treg maintenance in aged mice.Further, aged mice have increased serum levels of the pro-inflammatory cytokine IL-6, which contributed to increased ICOS expression on aged effector Treg.Additionally, IL-6 deficient mice have a significant reduction in Treg accrual with age.Taken together, our data show that IL-6 promotes effector Treg accrual, likely through the maintenance of ICOS expression.Together, the work in Chapter 3 and Chapter 4 broaden our understanding of aged Treg homeostasis.Further, our data have implications for manipulating Bim expression and Treg accrual to improve immune responses in the elderly.!iv! !
Author: Jana Raynor
Institution: University of Cincinnati
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1447259429, G9000304361
OpenAlex ID: W2608261521