Increased frequency of CD4+CD57+ senescent T cells in patients with newly diagnosed acute heart failure: exploring new pathogenic mechanisms with clinical relevance

Abstract

Recent animal studies showed T cells have a direct pathogenic role in the development of heart failure (HF). However, which subsets of T cells contribute to human HF pathogenesis and progression remains unclear. We characterized immunologic properties of various subsets of T cells and their clinical implications in human HF. Thirty-eight consecutive patients with newly diagnosed acute HF (21 males, mean age 66 ± 16 years) and 38 healthy control subjects (21 males, mean age 62 ± 12 years) were enrolled. We found that pro-inflammatory mediators, including CRP, IL-6 and IP-10 and the frequencies of CD57⁺ T cells in the CD4⁺ T cell population were significantly elevated in patients with acute HF compared to control subjects. A functional analysis of T cells from patients with acute HF revealed that the CD4⁺CD57⁺ T cell population exhibited a higher frequency of IFN-γ- and TNF-α- producing cells compared to the CD4⁺CD57^- T cell population. Furthermore, the frequency of CD4⁺CD57⁺ T cells at baseline and its elevation at the six-month follow-up were significantly related with the development of cardiovascular (CV) events, which were defined as CV mortality, cardiac transplantation, or rehospitalization due to HF exacerbation. In conclusion, CD4⁺CD57⁺ senescent T cells showed more inflammatory features and polyfunctionality and were associated with clinical outcome in patients with acute HF. More detailed study for senescent T cells might offer new opportunities for the prevention and treatment of human HF.

Figure 1

Pro-inflammatory mediators are elevated in patients with acute HF. Serum samples were obtained from healthy controls and patients with acute HF. (a) Enzyme-linked immunosorbent assay results show CRP concentrations. (b–f) Cytometric bead array results show (b) IL-6, (c) TNF-α, (d) MIG, (e) IP-10, and (f) MIP-1α concentrations. Medians and standard deviations are presented for each group. N.S., non-significant.

Figure 2

The frequencies of CD4⁺CD28^null and CD4⁺CD57⁺ T cells are elevated in patients with acute HF. (a,b) The percentages of (a) CD4⁺CD28^null T cells, (b) CD4⁺CD57⁺ T cells in the CD4⁺ T cell populations were determined in PBMCs from healthy controls and patients with acute HF. (c) A gating strategy for flow cytometry analysis is presented. (d,e) The percentages of (d) CD8⁺CD28^null T cells, and (e) CD8⁺CD57⁺ T cells in the CD8⁺ T cell populations were determined in PBMCs from healthy controls and patients with acute HF. Medians and standard deviations are presented for each group. N.S., non-significant.

Figure 3

The CD4⁺CD57⁺ T cell population exhibits higher frequencies of IFN-γ- and TNF-α-producing cells than the CD4⁺CD57⁻ T cell population. PBMCs were stimulated with anti-CD3 antibody, and intracellular cytokine staining was performed to detect IFN-γ and TNF-α. (a) The frequencies of IFN-γ⁺, TNF-α⁺, and double positive (IFN-γ⁺TNF-α⁺) cells are shown for CD4⁺CD57⁺ T-cell and CD4⁺CD57⁻ T-cell populations from patients with acute HF. (b) A gating strategy for flow cytometry analysis is presented. (c) The frequencies of IFN-γ⁺, TNF-α⁺, and double positive (IFN-γ⁺TNF-α⁺) cells are shown for CD4⁺CD28⁺ T-cell and CD4⁺CD28^null T-cell populations from patients with acute HF. (d) The frequencies of IFN-γ⁺ and TNF-α⁺ cells are shown for CD4⁺CD57⁺ T-cell and CD4⁺CD57⁻ T-cell populations from healthy individuals. (e) The frequencies of IFN-γ⁺ and TNF-α ⁺ cells among the CD4⁺CD57⁺ T-cell population were compared between healthy individuals and patients with acute HF.

Figure 4

The frequencies of CD4⁺CD57⁺ T cells at baseline and at the 6-month follow-up are related to clinical outcome in patients with acute HF. (a) Baseline frequencies of CD4⁺CD57⁺ T cells in PBMCs from patients with acute HF were compared between those without and those with CV events. Medians are presented for each group. (b) Cumulative Kaplan-Meier estimates of CV events in patients with acute HF are compared between patients with different baseline CD4⁺CD57⁺ T cell frequencies (according to the Youden index). (c) Baseline and 6-month CD4⁺CD57⁺ T cell frequencies in PBMCs from patients with acute HF are compared between those without and those with CV events. N.S., non-significant.