{'fraction_non_alphanumeric': 0.047481420313790254, 'fraction_numerical': 0.02023121387283237, 'mean_word_length': 4.278867102396514, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Abstract 429: Tnf Receptor-1 Dictates Life/death Decisions of Auto-reactive T-lymphocytes During Heart Failure


 Ischemic heart failure (HF) results in the activation of self-reactive CD4+ T-lymphocytes against unknown cardiac antigens. The mechanisms that mediate the survival of self-reactive T-cells during ischemic HF are not known. TNF mediated NF-kB signaling regulates cellular apoptotic pathways and T cells express high levels of TNF receptor-1 (TNFR1) during chronic heart failure. Thus, we hypothesized that TNFR1 regulates pro-apoptotic signaling through NF-kB and is critical for the clearance of self-reactive T-cells during HF. To test this, male WT or TNFR1
 -/-
 mice underwent coronary artery ligation to induce HF (10 wks post-ligation), followed by isolation and adoptive-transfer (AT) of splenic CD4+ T-cells (9X10
 6
 cells/mouse) into the tail-veins of naïve CD45.1 mice. Flow cytometric analysis showed ~7-fold higher levels of HF-activated TNFR1
 -/-
 T cells in recipient mice when compared with WT T-cells at 2d post-AT, and were not different between the 2-groups at 1 wk. Interestingly, TNFR1
 -/-
 T cells were significantly higher again at 2 wks (as compared to WT T-cells) and the levels were sustained for up to 14 wks post-AT. In contrast, donor WT T-cells were slowly cleared from the recipient mice. In addition, as compared to WT T-cells, ~11-fold higher levels of adoptively transferred TNFR1
 -/-
 T cells were observed in the spleens of recipient mice at 14 wks suggesting that TNFR1
 -/-
 T cells had higher propensity to seed into the lymphoid tissues. This data also suggests that TNFR1
 -/-
 T cells either have enhanced pro-survival pathways or were less prone to activation-induced cell death.
 In-vitro
 T-cell proliferation assays using anti-CD3/CD28 antibodies showed enhanced proliferation and expression of anti-apoptotic Bcl-xL upon treatment with a TNFR1 neutralization antibody corroborating
 in-vivo
 results. Intriguingly, as opposed to WT T-cells, adoptive transfer of HF-activated TNFR1
 -/-
 T-cells induced significant cardiac dysfunction and the ejection fraction (EF) of naïve recipient mice was significantly decreased from 63±6% to 45±6% at 14 weeks post-AT. Our data show that TNFR1 signaling regulates pro-vs anti-apoptotic pathways in a context-dependent manner and potentiate pathological phenotype of HF activated T-cells by enhancing their life-span.
