IL-6 and ICOS antagonize bim and promote regulatory T cell accrual with age

J Raynor, R Karns, M Almanan, KP Li… - The Journal of …, 2015 - journals.aai.org
J Raynor, R Karns, M Almanan, KP Li, S Divanovic, CA Chougnet, DA Hildeman
The Journal of Immunology, 2015journals.aai.org
Regulatory T cells (Tregs), a subset of CD4+ T cells, dramatically accumulate with age in
humans and mice and contribute to age-related immune suppression. Recently, we showed
that a majority of accumulating Tregs in aged mice expressed low levels of CD25, and their
accrual is associated with declining levels of IL-2 in aged mice. In this study, we further
investigated the origin of CD25 lo Tregs in aged mice. First, aged Tregs had high expression
of neuropilin-1 and Helios, and had a broad V β repertoire. Next, we analyzed the gene …
Abstract
Regulatory T cells (Tregs), a subset of CD4+ T cells, dramatically accumulate with age in humans and mice and contribute to age-related immune suppression. Recently, we showed that a majority of accumulating Tregs in aged mice expressed low levels of CD25, and their accrual is associated with declining levels of IL-2 in aged mice. In this study, we further investigated the origin of CD25 lo Tregs in aged mice. First, aged Tregs had high expression of neuropilin-1 and Helios, and had a broad V β repertoire. Next, we analyzed the gene expression profile of Tregs, naive T cells, and memory T cells in aged mice. We found that the gene expression profile of aged CD25 lo Tregs were more related to young CD25 lo Tregs than to either naive or memory T cells. Further, the gene expression profile of aged Tregs was consistent with recently described “effector” Tregs (eTregs). Additional analysis revealed that nearly all Tregs in aged mice were of an effector phenotype (CD44 hi CD62L lo) and could be further characterized by high levels of ICOS and CD69. ICOS contributed to Treg maintenance in aged mice, because in vivo Ab blockade of ICOSL led to a loss of eTregs, and this loss was rescued in Bim-deficient mice. Further, serum levels of IL-6 increased with age and contributed to elevated expression of ICOS on aged Tregs. Finally, Treg accrual was significantly blunted in aged IL-6–deficient mice. Together, our data show a role for IL-6 in promoting eTreg accrual with age likely through maintenance of ICOS expression.
journals.aai.org