Age-Associated Resident Memory CD8 T Cells in the Central Nervous System Are Primed To Potentiate Inflammation after Ischemic Brain Injury

Abstract

Aging is associated with an increase in basal inflammation in the central nervous system (CNS) and an overall decline in cognitive function and poorer recovery following injury. Growing evidence suggests that leukocyte recruitment to the CNS is also increased with normal aging, but to date, no systematic evaluation of these “age-associated” leukocytes have been performed. In this work the effect of aging on CNS leukocyte recruitment was examined. Aging was associated with an increased number of CD45hi leukocytes, primarily composed of conventional CD8+ T cells. These results were strain-independent and seen in both sexes. Intravascular labeling and immunohistology revealed the presence of parenchymal CD8+ T cells in several regions of the brain including the choroid plexus and meninges. These cells had effector memory (CD44+CD62L−) and tissue-resident phenotypes and expressed markers associated with T cell receptor (TCR) activation. Analysis of TCRvβ repertoire usage suggested that entry into the CNS is likely stochastic rather than antigen-driven. Correlational analyses revealed a positive association between CD8 T cell numbers and decreased pro-inflammatory function of microglia. However, the effects of cerebral ischemia and ex-vivo stimulation of these cells dramatically increased production of tumor necrosis factor (TNF), interferon gamma (IFNγ), and monocyte-chemotactic protein-1 (MCP-1/CCL2). Taken together, we identified a novel population of resident memory, immunosurveillant CD8 T cells that represent a hallmark of CNS aging and appear to modify microglia homeostasis under normal conditions, but are primed to potentiate inflammation and leukocyte recruitment following ischemic injury.

Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

“…Evidence suggests that aging impacts the baseline brain inflammatory profile (57)(58)(59)(60) and outcome of ischemic brain injury (61). In an effort to determine whether astrocytic IL-15 operates in the aged brain, we also compared stroke severity in aged GFAP-IL-15 tg and WT mice.…”

The effects of HIV and aging on subcortical shape alterations: A 3D morphometric study

“…Thus, it is possible that some of the underlying neuropathology driving these aging-related hypertrophies are also involved in the hypertrophy found in older HIV1 participants. Such age-related mechanisms may include increased microglia proliferation with age [Hua et al, 2012], morphologic hypertrophy of activated microglia [Streit et al, 2004;Flanary, 2005] leading to improper removal of damaged or senescent microglia [Mosher & Wyss-Coray, 2014], increased trafficking of peripheral leukocytes into the CNS [Ritzel et al, 2016], altered neuroprotective and inflammatory functions of microglia [Nakanishi & Wu, 2009;von Bernhardi et al, 2010] and inflammation-related (e.g., CD41 T lymphocyte) neurogenesis within healthy tissue [Kipnis et al, 2004;Ziv et al, 2006;Wolf et al, 2009; for a detailed review, please see Schwartz et al, 2013].…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…Increased CD8 + T cells in the aged CNS were associated with compromised proinflammatory functions in microglia. The primed microglia increased inflammation and leukocyte recruitment in the brain following stroke [196]. Comparing mononuclear phagocytes between young and old mice, aged macrophages, and microglia exhibited reduced motility in response to laser-induced injury and extracellular ATP [197].…”