Dietary selenium modulates activation and differentiation of CD4+ T cells in mice through a mechanism involving cellular free thiols

Abstract

The immune-enhancing effects of selenium (Se) supplementation make it a promising complementary and alternative medicine modality for boosting immunity, although mechanisms by which Se influences immunity are unclear. Mice fed low (0.08 mg/kg), medium (0.25 mg/kg), or high (1.0 mg/kg) Se diets for 8 wk were challenged with peptide/adjuvant. Antigen-specific CD4(+) T cell responses were increased in the high Se group compared with the low and medium Se groups. T cell receptor signaling in ex vivo CD4(+) T cells increased with increasing dietary Se, with all 3 groups differing from one another in terms of calcium mobilization, oxidative burst, translocation of nuclear factor of activated T cells, and proliferation. The high Se diet increased expression of interleukin (IL)-2 and the high affinity chain of the IL-2 receptor compared with the low and medium Se diets. The high Se diet skewed the T helper (Th)1/Th2 balance toward a Th1 phenotype, leading to higher interferon-gamma and CD40 ligand levels compared with the low and medium Se diets. Prior to CD4(+) T cell activation, levels of reactive oxygen species did not differ among the groups, but the low Se diet decreased free thiols compared with the medium and high Se diets. Addition of exogenous free thiols eliminated differences in CD4(+) T cell activation among the dietary groups. Overall, these data suggest that dietary Se levels modulate free thiol levels and specific signaling events during CD4(+) T cell activation, which influence their proliferation and differentiation.

FIGURE 1

Selenoenzyme activity in erythrocytes (A), plasma (B), and CD4⁺ T cells (C,D), and in vivo CD4⁺ T cell responses (E) in mice fed low, medium, or high Se diets for 8 wk. Values are means + SE, n = 3 (A–D) and 10 (E). For all graphs, means without a common letter differ, P < 0.05.

FIGURE 2

TCR signal strength as determined by Ca²⁺ flux (A), oxidative burst (B), and NFAT translocation (C) in CD4⁺ T cells from mice fed low, medium, or high Se diets for 8 wk. (A) For each dietary group, cells were pooled from 3 mice and results represent 3 independent experiments. (B,C) Values are means + SE, n = 3. For all graphs, means without a common letter differ, P < 0.05.

FIGURE 3

IL-2 mRNA (A), CD25 mRNA (B), CD25 surface expression (C), and cell proliferation (D) for TCR-stimulated CD4⁺ T cells from mice fed low, medium, or high Se diets for 8 wk. Values are means + SE, n = 3 (A,B,D) and 5 (C). For A, means at each time point without a common letter differ, P < 0.05. For B–D, means without a common letter differ, P < 0.05.

FIGURE 4

IFNγ mRNA (A), IL-4 mRNA (B), and surface expression of CD40L (C) for TCR-stimulated CD4⁺ T cells from mice fed low, medium, or high Se diets for 8 wk. Values are means + SE, n = 3 (A,B) and 5 (C,D). For A and B, means at each time point without a common letter differ, P < 0.05. For B–D, means without a common letter differ, P < 0.05.

FIGURE 5

Free thiols (A) and GSH levels (B) and effects of exogenous free thiols on TCR-induced proliferation (C) for CD4+ T cells from mice fed low, medium, or high Se diets for 8 wk. Values are the mean + SE, n = 3 (A,B). Means without a common letter differ, P < 0.05. For C, values are the mean + SE, n = 11. P-values from the 2-way ANOVA were: diet, P < 0.001; NAC, P < 0.001; interaction, P < 0.001. Means without a common letter differ, P < 0.05.