TNF-α protects from exacerbated myocarditis and cardiac death by suppressing expansion of activated heart-reactive CD4⁺ T cells

Tumour necrosis factor α (TNF-α) represents a classical pro-inflammatory cytokine, and its increased levels positively correlate with the severity of many cardiovascular diseases. Surprisingly, some heart failure patients receiving high doses of anti-TNF-α antibodies showed serious health worsening. This work aimed to examine the role of TNF-α signalling on the development and progression of myocarditis and heart-specific autoimmunity.

Mice with genetic deletion of TNF-α (Tnf^+/− and Tnf^−/−) and littermate controls (Tnf^+/+) were used to study myocarditis in the inducible and the transgenic T cell receptor (TCRM) models. Tnf^+/− and Tnf^−/− mice immunized with α-myosin heavy chain peptide (αMyHC) showed reduced myocarditis incidence, but the susceptible animals developed extensive inflammation in the heart. In the TCRM model, defective TNF-α production was associated with increased mortality at a young age due to cardiomyopathy and cardiac fibrosis. We could confirm that TNF-α as well as the secretome of antigen-activated heart-reactive effector CD4⁺ T (T_eff) cells effectively activated the adhesive properties of cardiac microvascular endothelial cells (cMVECs). Our data suggested that TNF-α produced by endothelial in addition to T_eff cells promoted leucocyte adhesion to activated cMVECs. Analysis of CD4⁺ T lymphocytes from both models of myocarditis showed a strongly increased fraction of T_eff cells in hearts, spleens, and in the blood of Tnf^+/− and Tnf^−/− mice. Indeed, antigen-activated Tnf^−/− T_eff cells showed prolonged long-term survival and TNF-α cytokine-induced cell death of heart-reactive T_eff.

TNF-α signalling promotes myocarditis development by activating cardiac endothelial cells. However, in the case of established disease, TNF-α protects from exacerbating cardiac inflammation by inducing activation-induced cell death of heart-reactive T_eff. These data might explain the lack of success of standard anti-TNF-α therapy in heart failure patients and open perspectives for T cell–targeted approaches.