Role, function and regulation of the thymocyte selection-associated high mobility group box protein in CD8+ T cell exhaustion

We previously reported an early surge in high mobility group box protein 1 (HMGB1) levels in a polytrauma (PT) rat model. This study investigates the association of HMGB1 levels in mediating PT associated dysregulated immune responses and its influence on the cellular levels of receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). Using the same PT rat model treated with anti-HMGB1 polyclonal antibody, we evaluated changes in circulating inflammatory cytokines, monocytes/macrophages and T cells dynamics and cell surface expression of RAGE and TLR4 at 1, 3, and 7 days post-trauma (dpt) in blood and spleen. Notably, PT rats demonstrating T helper (Th)1 and Th2 cells type early hyper-inflammatory responses also exhibited increased monocyte/macrophage counts and diminished T cell counts in blood and spleen. In blood, expression of RAGE and TLR4 receptors was elevated on CD68+ monocyte/macrophages and severely diminished on CD4+ and CD8+ T cells. Neutralization of HMGB1 significantly decreased CD68+ monocyte/macrophage counts and increased CD4+ and CD8+ T cells, but not γδ+TCR T cells in circulation. Most importantly, RAGE and TLR4 expressions were restored on CD4+ and CD8+ T cells in treated PT rats. Overall, findings suggest that in PT, the HMGB1 surge is responsible for the onset of T cell exhaustion and dysfunction, leading to diminished RAGE and TLR4 surface expression, thereby possibly hindering the proper functioning of T cells.

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Faculty Opinions recommendation of Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1142885.619466 ◽

2009 ◽

Author(s):

Jay Berzofsky

Keyword(s):

T Cell ◽

Viral Infection ◽

Cd8 T Cell ◽

Chronic Viral Infection ◽

T Cell Exhaustion ◽

Inhibitory Receptors ◽

Cell Exhaustion

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Faculty Opinions recommendation of Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1142885.606960 ◽

2009 ◽

Author(s):

Andrew Badley

Keyword(s):

T Cell ◽

Viral Infection ◽

Cd8 T Cell ◽

Chronic Viral Infection ◽

T Cell Exhaustion ◽

Inhibitory Receptors ◽

Cell Exhaustion

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Faculty Opinions recommendation of Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1142885.599974 ◽

2009 ◽

Author(s):

Allan Zajac

Keyword(s):

T Cell ◽

Viral Infection ◽

Cd8 T Cell ◽

Chronic Viral Infection ◽

T Cell Exhaustion ◽

Inhibitory Receptors ◽

Cell Exhaustion

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The Potential of T Cell Factor 1 in Sustaining CD8+ T Lymphocyte-Directed Anti-Tumor Immunity

Cancers ◽

10.3390/cancers13030515 ◽

2021 ◽

Vol 13 (3) ◽

pp. 515

Author(s):

Sungmin Jung ◽

Jea-Hyun Baek

Keyword(s):

T Cell ◽

Tumor Immunity ◽

T Lymphocyte ◽

Critical Role ◽

Cd8 T Cell ◽

Immune Checkpoint Blockade ◽

Viral Escape ◽

T Cell Exhaustion ◽

Cell Exhaustion ◽

T Cell Factor

T cell factor 1 (TCF1) is a transcription factor that has been highlighted to play a critical role in the promotion of T cell proliferation and maintenance of cell stemness in the embryonic and CD8+ T cell populations. The regulatory nature of TCF1 in CD8+ T cells is of great significance, especially within the context of T cell exhaustion, which is linked to the tumor and viral escape in pathological contexts. Indeed, inhibitory signals, such as programmed cell death 1 (PD-1) and cytotoxic-T-lymphocyte-associated protein 4 (CTLA-4), expressed on exhausted T lymphocytes (TEX), have become major therapeutic targets in immune checkpoint blockade (ICB) therapy. The significance of TCF1 in the sustenance of CTL-mediated immunity against pathogens and tumors, as well as its recently observed necessity for an effective anti-tumor immune response in ICB therapy, presents TCF1 as a potentially significant biomarker and/or therapeutic target for overcoming CD8+ T cell exhaustion and resistance to ICB therapy. In this review, we aim to outline the recent findings on the role of TCF1 in T cell development and discuss its implications in anti-tumor immunity.

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