Age-related inflammation (so-called inflammaging) is associated with many deleterious processes in the elderly, including Alzheimer’s disease, cardiovascular disease, and general frailty. Declining immune function is also well described in the elderly, and leads to increased risk and severity of infection, poorer control of cancer, and impaired responses to vaccination. While there is clearly cell-intrinsic immune dysfunction with age, our and others data have revealed that cell extrinsic mechanisms also play significant roles.
Our long-term goal is to understand the mechanisms underlying the dysregulation of immune responses in aging and develop therapeutic strategies to enhance protective immune responses in the elderly.
In close collaboration with the Chougnet lab, we have discovered that two distinct types of regulatory T cells accumulate with age, classical FoxP3+ Tregs and a novel population of IL-10-secreting CD4+ T follicular helper cells. Current studies are investigating the accumulation and function of both of these cells in aged mice and humans.
In addition to accumulation of suppressive T cell populations, aging is also associated with decreased function of antigen-presenting cells, including dendritic cells (DCs). A key aspect of DC function is their capacity to “cross-present” cell-associated Ag to CD8+T cells, a process that is required to cross-prime CD8+T cell responses against tumors or intra-cellular pathogens. However, the effect of aging on the acquisition, processing, and presentation of cell-associated Ags by primary DCs has barely been studied. We recently uncovered that aging significantly reduced the cross-presenting and cross-priming capacity of the DC subsets the most efficient at carrying out this important task (CD8αDCs and merocytic DCs). Current studies will investigate mechanisms that control defective antigen uptake and processing in aged DCs.
RO1 AG033057 - Homeostasis and function of regulatory T cells in aging. Sept 15, 2009 - July 31st, 2017. NIH/NIA. Co-PIs: Chougnet, Hildeman
RO1 AG053498 - Metabolic alterations in age-associated dendritic cell dysfunction. Co-PIs: Chougnet, Hildeman
Mechanisms underlying Treg accumulation with age.