TNFR1 Contributes to Activation-Induced Cell Death of Pathological CD4⁺ T Lymphocytes During Ischemic Heart Failure

Area of Science:

• Immunology
• Cardiovascular Biology
• T cell biology

Background:

• CD4+ T cells become pathogenic in heart failure (HF).
• Expression of tumor necrosis factor-alpha (TNF-α) and its receptor TNFR1 increases in HF-activated CD4+ T cells.
• The role of the TNF-α/TNFR1 axis in T cell activation and proliferation during HF is not well understood.

Purpose of the Study:

• To investigate the function of the TNF-α/TNFR1 axis in regulating the activation, proliferation, and survival of CD4+ T cells in the context of heart failure.
• To determine if TNFR1 signaling influences the pathological activity of CD4+ T cells during HF.

Main Methods:

• Investigated TNFR1 signaling in CD4+ T cells from HF patients.
• Utilized ex vivo T cell activation with TNFR1 neutralization.
• Employed in vivo adoptive transfer models using TNFR1-deficient (TNFR1-/-) CD4+ T cells from HF models.
• Assessed T cell proliferation, prosurvival signaling, CD69 expression, and pathological activity.

Main Results:

• TNFR1 neutralization during ex vivo T cell activation augmented prosurvival and proliferative signaling.
• Loss of TNFR1 in adoptively transferred HF-activated CD4+ T cells (in vivo) also enhanced their prosurvival and proliferative signaling.
• TNFR1 neutralization did not alter CD69 expression, a marker of T cell activation.
• Pathological activity of HF-activated CD4+ T cells was not affected by TNFR1 neutralization or TNFR1 deficiency.

Conclusions:

• During heart failure, TNFR1 acts as a crucial regulator that suppresses prosurvival and proliferative signals in CD4+ T cells.
• Targeting TNFR1 may offer therapeutic potential for modulating T cell responses in HF, but its effect on pathological activity needs careful consideration.