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Updated: May 22, 2026
Measuring Mitochondrial Function of Naïve and Effector CD8 T Cells
Published on: March 28, 2025
Up-regulation of mitofusin-2 protects CD4+ T cells from HMGB1-mediated immune dysfunction partly through Ca(2+)-NFAT
Guang-ju Zhao1, Yong-ming Yao, Zhong-qiu Lu
1Emergency Department, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou 325000, PR China.
Abstract:
High mobility group box 1 protein (HMGB1) was recently discovered to be a critical late-acting cytokine and innate immune-modulating factor in sepsis, but the potential role and mechanism of HMGB1 in adaptive immunity remains elusive. The present study demonstrated that HMGB1 had a dual influence on immune function of CD4(+) T lymphocytes. Low dose of HMGB1 had no effect on the proliferation activity of CD4(+) T lymphocytes, but the Th1 cytokines production was increased. In contrast, treatment with high amount of HMGB1 suppressed the proliferative response and induced Th2 polarization of CD4(+) T lymphocytes. We found that the expression of mitofusin-2 (Mfn2; also named hyperplasia suppressor gene), a member of the mitofusin family, was decreased in CD4(+) T lymphocytes when stimulated with high dose of HMGB1. Up-regulation of Mfn2 attenuated the suppressive effect of HMGB1 on CD4(+) T lymphocytes, which was associated with profound elevation of intracellular calcium concentration ([Ca(2+)](i)) and nuclear factor of activated T cells (NFAT) activity. These results indicate that HMGB1 have a direct role on adaptive immunity, and the decrease of Mfn2 expression may be a major cause of HMGB1-mediated immune dysfunction and Ca(2+)-NFAT signaling defect of CD4(+) T lymphocytes.
Insights
High mobility group box 1 protein (HMGB1) impacts CD4(+) T cells differently based on dose. High HMGB1 levels impair T cell proliferation and promote Th2 responses by reducing mitofusin-2 (Mfn2).
Area of Science:
- Immunology
- Cell Biology
Background:
- High mobility group box 1 protein (HMGB1) is a known innate immune modulator in sepsis.
- The role of HMGB1 in adaptive immunity, particularly T cell responses, is not well understood.
Purpose of the Study:
- To investigate the dual effects of HMGB1 on CD4(+) T lymphocyte immune function.
- To elucidate the underlying molecular mechanisms, focusing on mitofusin-2 (Mfn2) and calcium signaling.
Main Methods:
- Treatment of CD4(+) T lymphocytes with varying doses of HMGB1.
- Assessment of T cell proliferation and cytokine production (Th1/Th2 balance).
- Analysis of Mfn2 expression, intracellular calcium levels ([Ca(2+)](i)), and NFAT activity.
Main Results:
- Low-dose HMGB1 enhanced Th1 cytokine production without affecting proliferation.
- High-dose HMGB1 suppressed proliferation and induced Th2 polarization.
- High-dose HMGB1 decreased Mfn2 expression, leading to impaired Ca(2+)-NFAT signaling.
Conclusions:
- HMGB1 directly influences adaptive immunity, exhibiting dose-dependent effects on CD4(+) T cells.
- Reduced Mfn2 expression is a key factor in HMGB1-induced immune dysfunction and signaling defects in T cells.
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