Abstract
BackgroundThe etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Gut tissue-resident memory T cells play critical roles in mediating protective immunity and in maintaining gut homeostasis, yet few studies have investigated the effect of aging on human gut T cell immunity. To determine if aging impacted CD4 T cell immunity in the human large intestine, we utilized multi-color flow cytometry to measure colonic lamina propria (LP) CD4 T cell frequencies and immune-modulatory marker expression in younger (mean ± SEM: 38 ± 1.5 yrs) and older (77 ± 1.6 yrs) adults. To determine cellular specificity, we evaluated colon LP CD8 T cell frequency and phenotype in the same donors. To probe tissue specificity, we evaluated the same panel of markers in peripheral blood (PB) CD4 T cells in a separate cohort of similarly aged persons.ResultsFrequencies of colonic CD4 T cells as a fraction of total LP mononuclear cells were higher in older persons whereas absolute numbers of colonic LP CD4 T cells per gram of tissue were similar in both age groups. LP CD4 T cells from older versus younger persons exhibited reduced CTLA-4, PD-1 and Ki67 expression. Levels of Bcl-2, CD57, CD25 and percentages of activated CD38+HLA-DR+ CD4 T cells were similar in both age groups. In memory PB CD4 T cells, older age was only associated with increased CD57 expression. Significant age effects for LP CD8 T cells were only observed for CTLA-4 expression, with lower levels of expression observed on cells from older adults.ConclusionsGreater age was associated with reduced expression of the co-inhibitory receptors CTLA-4 and PD-1 on LP CD4 T cells. Colonic LP CD8 T cells from older persons also displayed reduced CTLA-4 expression. These age-associated profiles were not observed in older PB memory CD4 T cells. The decline in co-inhibitory receptor expression on colonic LP T cells may contribute to local and systemic inflammation via a reduced ability to limit ongoing T cell responses to enteric microbial challenge.
Highlights
The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver
Our previous study suggested that disruption of gut homeostasis and its link to systemic inflammation occurs as part of human aging whereby plasma biomarkers of epithelial barrier damage and microbial translocation increased with age similar to other indicators of inflammaging (IL-6, C-reactive protein [CRP]) in persons aged 20–100 years [10]
In a recent study investigating the impact of age on human small intestine T cells, we demonstrated that jejunum lamina propria (LP) CD4 T cells from older persons (≥65 yrs) displayed phenotypic and functional differences versus those from younger persons (≤45 yrs) including reduced expression of the co-inhibitory molecule CTLA-4, increased spontaneous cell death and reduced frequencies of T helper 17 cells [18]
Summary
The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Older non-human primates had greater systemic inflammation, higher levels of biomarkers indicative of microbial translocation and intestinal barrier dysfunction, observations supported by increased gut permeability to large molecules [7,8,9]. Our previous study suggested that disruption of gut homeostasis and its link to systemic inflammation occurs as part of human aging whereby plasma biomarkers of epithelial barrier damage and microbial translocation increased with age similar to other indicators of inflammaging (IL-6, C-reactive protein [CRP]) in persons aged 20–100 years [10]. Few studies have investigated how aging directly impacts human intestinal immunity
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