Abstract
There is increasing evidence that in humans the adaptive immunological system can influence cognitive functions of the brain. We have undertaken a comprehensive immunological analysis of lymphocyte and monocyte populations as well as of HLA molecules expression in a cohort of elderly volunteers (age range, 64–101) differing in their cognitive status. Hereby, we report on the identification of a novel signature in cognitively impaired elderly characterized by: (1) elevated percentages of CD8+ T effector-memory cells expressing high levels of the CD45RA phosphate receptor (Temra hi); (2) high percentages of CD8+ T cells expressing high levels of the CD8β chain (CD8βhi); (3) augmented production of IFNγ by in vitro activated CD4+ T cells. Noteworthy, CD3+CD8+ Temra hi and CD3+CD8βhi cells were associated with impaired cognition. Cytomegalovirus seroprevalence showed that all volunteers studied but one were CMV positive. Finally, we show that some of these phenotypic and functional features are associated with an increased frequency of the HLA-B8 serotype, which belongs to the ancestral haplotype HLA-A1, Cw7, B8, DR3, DQ2, among cognitively impaired volunteers. To our knowledge, this is the first proof in humans linking the amount of cell surface CD45RA and CD8β chain expressed by CD8+ Temra cells, and the amount of IFNγ produced by in vitro activated CD4+ T cells, with impaired cognitive function in the elderly.
Highlights
A possible role for the immunological system in maintaining central nervous system (CNS) homeostasis has long been a matter of debate
Our results show for the first time that a subpopulation of CD3+CD8+ T cells characterized by the expression at the plasma membrane of high levels CD45RA (CD8+ TEMRAhi) and high levels of the CD8b chain (CD3+CD8bhi) is overrepresented in elderly people with impaired cognitive status
We show that CD4+ T cells from elderly people with impaired brain cognitive status activated in vitro with PMA/Ionomycin produce about two-fold more IFNg than elderly people with unimpaired brain cognitive status
Summary
A possible role for the immunological system in maintaining central nervous system (CNS) homeostasis has long been a matter of debate. Similar studies in humans are lacking, there is recent evidence suggesting that innate and adaptive immunological cells modulate hippocampal neurogenesis and behavior through notwell understood mechanisms [8] In this respect, recent reports have shown that the human brain is inhabited by a large fraction of effector-memory CD8+ T cells expressing or not the CD45RA isoform, with some becoming tissue-resident upon expression of CD69 and CD103 [9]. Resident CD8+CD69+ T cells in the human brain show increased expression of tissue homing and inhibitory receptors, and are low producers of granzymes [9] Some of these brain-resident CD8+ T cell features are shared by certain populations of peripheral blood effector-memory CD8+ T cells [10, 11], and are in accordance with experimental evidence suggesting that peripheral blood circulating CD8+ TEMRA cells migrate to the brain parenchyma [12, 13]. A recent seminal study in Alzheimer’s disease patients has identified an immune signature that consists of expansions of CD8+ TEMRA cells in peripheral blood as well as in the cerebrospinal fluid produced by the choroid plexus [16]
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