Imbalance of Circulating Th17 and Regulatory T Cells in Alzheimer’s Disease: A Case Control Study

Abstract

The neuropathological hallmarks of Alzheimer’s disease (AD), i.e., neuritic plaques and neurofibrillary tangles, consist of beta amyloid peptides (Aβ) and hyperphosphorylated Tau. These are accompanied by reactive microglia and astrocytes in the vicinity of the neuritic plaques and by changes to the peripheral immune system, e.g., an increase of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in the peripheral blood. To address a potential involvement of peripheral T helper cell (Th) subsets in AD, we conducted a case control study with 54 individuals with AD dementia (n = 14), with mild cognitive impairment (MCI) due to AD (MCIAD, n = 14), with MCI unlikely due to AD (MCIother, n = 13), and controls without cognitive impairment (controls, n = 13). The proportions of CD3+CD8−IL-17A+IFNγ− Th17 cells, CD3+CD8−IL-17A−IFNγ+ Th1 cells, and CD4+CD127lowCD25+ regulatory T cells (Tregs) were assessed by flow cytometry. In addition, the correlations of the proportions of Th subsets to cerebrospinal fluid biomarkers were studied. CD3+CD8−IL-17A+IFNγ− Th17 cells were significantly increased in subjects with MCIAD compared to age- and sex-matched subjects with MCIother and controls (MCIAD mean = 1.13, SD = 0.77; MCIother mean = 0.58, SD = 0.28; and controls mean = 0.52, SD = 0.22; p = 0.008). The proportion of CD4+CD127lowCD25+ Tregs was not altered between the different groups, but it significantly positively related with the levels of total Tau and pTau181 (rTreg|totalTau = 0.43, p = 0.021, n = 28; rTreg|pTau181 = 0.46; p = 0.024, n = 28) in subjects with AD but not in nonAD controls (rTreg|totalTau = −0.51, p = 0.007, n = 26). The increase of circulating CD3+CD8−IL-17A+IFNγ− Th17 cells in the early stages of AD and the association of CD4+CD127lowCD25+ Tregs with neurodegeneration marker Tau may indicate that the adaptive immune system relates to neuropathological changes in AD.

Influenza vaccination in early Alzheimer’s disease rescues amyloidosis and ameliorates cognitive deficits in APP/PS1 mice by inhibiting regulatory T cells

“…Recently, several studies have suggested that the frequencies of Th17 and the Th17/Treg ratio are enhanced in AD and/or MCI patients [56,57], which seems to contradict our results. However, our data show that the proportion of CD4 + IL-17A + Th17 cells was not altered among the WT, WT+IIV, AD and AD+IIV groups.…”

“…Therefore, our results suggest that the higher IIV-induced Th17/Treg ratio is due to the decreased proportion of Tregs rather than higher Th17 proportion. Regarding the different Th17 proportion in AD patients reported in recent studies [56,57] and our results, a possible explanation for the differences is related to the different research subjects and immune cells (PBMC vs. spleen cells). It could be valuable to obtain similar data (Th17/Treg ratio) using different transgenic AD mouse models (3xFAD etc.)…”

The intestinal expansion of TCRγδ+ and disappearance of IL4+ T cells suggest their involvement in the evolution from potential to overt celiac disease

“…The frequency of IL4‐, IL17A‐, and IFN‐γ‐positive cells was analyzed in all three children groups, while IL21‐positive cells were analyzed only in children with CD (overt‐ and potential‐CD). Because it has been documented a downregulation of the expression of CD4 molecule on cell membrane after a strong stimulation (PMA/ionomycin mitogens) , the analysis of cytokine positive cells was performed in the gate of CD3 + CD8 + and CD3 + CD8 − T cell subsets.…”

Deep cervical lymph node ligation aggravates AD‐like pathology of APP/PS1 mice

“…A decrease of CD4+CD25 high T cells, an increase in CD4+Foxp3+ Tregs, but no changes in CD8+ T cell subsets, have been observed in Alzheimer’s dementia . Recently, a case control study reported an increase in circulating T helper 17 cells in the early stages of AD and an association of CD4+ CD127 low CD25+ regulatory T cells (Trges) with neurodegeneration marker Tau . In animal experiments, Tregs are shown to slow the AD‐like progression and restore cognitive function of APP/PS1 mice .…”