T Cell Recruitment in the Brain during Normal Aging

Abstract

Aging-related changes in the peripheral immune response are well documented, but less is known about changes of the immune response in the central nervous system. Reactivity of microglia, effectors of the brain innate immunity, is known to increase in the aged brain, but little attention has been hitherto devoted to T cell recruitment. Data in rodents point to a gradual enhancement of T cell homing to the brain in the steady state since the middle age. Experimental findings also point to enhanced transmigration of lymphocytes as part of an amplified response of the aging brain to acute exogenous inflammatory insults. Thus, available data support the capacity of the aged brain to mount a robust immune response, in contrast with peripheral immunity decline, and indicate that such central response involves recruitment of lymphocytes. These findings open many questions, including blood-brain barrier molecular regulation and infiltrated T cell subtypes during normal aging. The crosstalk between T cells, glia, and neurons also remains to be clarified in the aged brain parenchyma. This intercellular dialogue and related signaling could be relevant for both protection of the aged brain and its vulnerability to neurological disease.

Keywords: blood-brain barrier; central nervous system; glia; immunity; inflammation; lymphocytes.

Figure 1

Schematic representation of the normal organization of the parenchyma and blood-brain barrier (BBB) of the young adult (left) and aged (right) brain, as derived from studies that are here reviewed. In the brain parenchyma, a single neuron (light brown), astrocytes (orange), and microglia (blue) are represented; oligodendrocytes and perivascular macrophages are not shown. Astrocytic endfeet contribute to the formation of the BBB, together with tight junctions of endothelial cells of cerebral microvessels and their respective basement membranes (represented for simplicity as a single green band). In the aged brain compared to the young brain, astrocytes (depicted as hypertrophic) and microglia (hypertrophic with stout, less ramified processes) show a low grade activation in the steady state; in addition, as shown in the inset (upper right) tight-junctional assemblies between endothelial cells may be altered. At variance with the young brain in which T cell (purple) entry is restricted by the BBB, T cells can infiltrate the aged brain parenchyma in low numbers. Access to dendritic cells (one dendritic cell is shown in light green) may also be facilitated in the aged brain. Adapted and modified from Bentivoglio et al. (2011).