Is ageing associated with a shift in the balance between Type 1 and Type 2 cytokines in humans?

Abstract

The balance between Type 1 and Type 2 cytokines is important for the outcome of several infectious diseases. As elderly humans show increased morbidity and mortality from infectious diseases, this study tests if ageing is associated with a change towards Type 2 dominance in T cells. Expression of IFN-gamma, and IL-4 was measured in CD4+ and CD8+ T cells by flow cytometry in three groups: young controls (n=28), 81-year-olds (n=22), and centenarians (n=25). The major findings were that the percentage of IFN-gamma+ as well as IL-4+ T cells was increased in aged subjects. Furthermore, after adjusting for decreased lymphocyte counts in the elderly, the concentration in the blood of IFN-gamma+ and IL-4+ CD8+ T cells was still increased in the 81-year-olds. In centenarians, a shift towards a relative dominance of Type 2 cytokine expression was found within CD8+ T cells. Furthermore, the percentage of T cells with cytokine expression was closely correlated to the in vivo expression of CD95 and CD45RO. In conclusion, we found some evidence for an age-related shift towards a Type 2 cytokine profile.

Fig. 1

Cytokine expression in T lymphocytes. Cytokine expression among CD4⁺ and CD8⁺ T cells was detected by flow cytometry after 4 h of stimulation with PMA and ionomycin. Young n = 24, 81-year-old n = 14, 100-year-old n = 25. (a) The percentage of IFN-γ⁺ cells among CD4⁺ and CD8⁺ lymphocytes. (b) The percentage of IL-4⁺ cells among CD4⁺ and CD8⁺ lymphocytes. (c) The number of IFN-γ producing cells/ml blood. (d) The number of IL-4 producing cells/ml blood. (e) IFN-γ/IL-4 ratio within CD4⁺ and CD8⁺ cells. Geometric means and 95% confidence intervals are shown. * denotes a significant difference (P < 0·05) from the young group; # denotes a significant difference (P < 0·05) from the 81-year-old group; □ 21–30 years; 81 years; ▪ 100 years.

Fig. 2

Cytokine production in BMNC supernatants following PMA + ionomycin stimulation. Cytokine production was detected by ELISA after stimulation for 5 and 48 h. IFN-γ; Young, n = 23; 81-year-old, n = 10; 100-year-old, n = 18. IL-4; Young, n = 17; 81-year-old, n = 8; 100-year-old, n = 18. Geometric means and 95% confidence intervals are shown. * denotes a significant difference (P < 0·05) from the young group; □ 21–30 years; 81 years; ▪ 100 years.

Fig. 3

Correlation between the percentage of cytokine-expressing lymphocytes and cytokine levels in culture supernatants. BMNC for intracellular cytokine detection and BMNC for supernatants were stimulated by using exactly the same amounts of PMA + ionomycin. The percentage of all lymphocytes expressing intracellular cytokines was correlated with cytokine levels in supernatants after 5 h. The supernatants after 5 h were ln transformed. Each independent variable was tested for an interaction with age groups. No interactions were found, and accordingly age groups were pooled. Geometric means and 95% confidence intervals are shown.