Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults

Abstract

Background 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. 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. Results Frequencies 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. Conclusions Greater 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.

Phenotypic and functional alterations of monocyte subsets with aging

“…Previous studies have demonstrated that both HLA-DR and co-inhibitory molecules regulate innate inflammatory responses in different manners [ 40 – 42 ]. Since HLA-DR crosslinking can generate intracellular signals to induce TNF-α release in monocytes, enhanced HLA-DR expression is consistent with amplified inflammatory responses in aged monocytes [ 43 ].…”

Granzyme B + CD4 T cells accumulate in the colon during chronic HIV-1 infection

“…Given that the majority of colonic CD4 T cells are effector memory cells, 44 we also evaluated the expression of GZB in memory and naïve PB CD4 T cell populations (Figure S5). Percentages of naïve (CCR7 + CD45RO − ), central memory (CCR7 + CD45RO + ; CM) and effector memory (CCR7 − CD45RO + ; EM) PB CD4 T cells were generally similar between controls and PWH ( Figure 2b ).…”

“…Instead, we noted a positive association between frequencies of blood effector memory GZB + CD4 T cells and colonic GZB + CD4 T cells in PWH. Human gut CD4 T cells are mostly composed of effector memory cells, 44 and studies in mice demonstrated that tissue-resident CD8 + T cells can contribute to the circulating memory T cell pool following activation. 45 Thus, the HIV-1-associated increase in blood GZB + CD4 T cells may reflect recently activated gut GZB + CD4 T cells migrating into the systemic circulation rather than differentiation of these cells in peripheral blood.…”

The impact of aging on intestinal mucosal immune function and clinical applications

“…PD-1 and CTLA-4, as the inhibitory moleculules, show reduced expression. Also, the expression of Ki67 is decreased, which is associated with steady-state proliferation and renewal of cells ( 63 , 64 ). The inhibitory molecules CTLA-4 and PD-1 can inhibit T cell activation and T cell responses through different mechanisms ( 65 , 66 ).…”

“…Also, Ki67 expression is generally low in LP CD4 + T cells from young individuals as well. So, it is difficult to determine the significance of further reduction of Ki67 in aging LP CD4 + T cells ( 63 , 64 ). In addition, aging reduces the frequency and function of LP CD4 Th17 cell, which is important to antigen-specific immune responses and mucosal barrier integrity.…”