RIPK1 protects naive and regulatory T cells from TNFR1-induced apoptosis.
Jelle HuysentruytWolf SteelsMario Ruiz PerezBruno VerstraetenMike VadiTatyana DivertKayleigh FliesNozomi TakahashiBart N LambrechtWim DeclercqTom Vanden BergheJonathan MaelfaitPeter VandenabeelePeter TougaardPublished in: Cell death and differentiation (2024)
The T cell population size is stringently controlled before, during, and after immune responses, as improper cell death regulation can result in autoimmunity and immunodeficiency. RIPK1 is an important regulator of peripheral T cell survival and homeostasis. However, whether different peripheral T cell subsets show a differential requirement for RIPK1 and which programmed cell death pathway they engage in vivo remains unclear. In this study, we demonstrate that conditional ablation of Ripk1 in conventional T cells (Ripk1 ΔCD4 ) causes peripheral T cell lymphopenia, as witnessed by a profound loss of naive CD4 + , naive CD8 + , and FoxP3 + regulatory T cells. Interestingly, peripheral naive CD8 + T cells in Ripk1 ΔCD4 mice appear to undergo a selective pressure to retain RIPK1 expression following activation. Mixed bone marrow chimeras revealed a competitive survival disadvantage for naive, effector, and memory T cells lacking RIPK1. Additionally, tamoxifen-induced deletion of RIPK1 in CD4-expressing cells in adult life confirmed the importance of RIPK1 in post-thymic survival of CD4 + T cells. Ripk1 K45A mice showed no change in peripheral T cell subsets, demonstrating that the T cell lymphopenia was due to the scaffold function of RIPK1 rather than to its kinase activity. Enhanced numbers of Ripk1 ΔCD4 naive T cells expressed the proliferation marker Ki-67 + despite the peripheral lymphopenia and single-cell RNA sequencing revealed T cell-specific transcriptomic alterations that were reverted by additional caspase-8 deficiency. Furthermore, Ripk1 ΔCD4 Casp8 ΔCD4 and Ripk1 ΔCD4 Tnfr1 -/- double-knockout mice rescued the peripheral T cell lymphopenia, revealing that RIPK1-deficient naive CD4 + and CD8 + cells and FoxP3 + regulatory T cells specifically die from TNF- and caspase-8-mediated apoptosis in vivo. Altogether, our findings emphasize the essential role of RIPK1 as a scaffold in maintaining the peripheral T cell compartment and preventing TNFR1-induced apoptosis.
Keyphrases
- induced apoptosis
- regulatory t cells
- single cell
- endoplasmic reticulum stress
- cell death
- signaling pathway
- hiv infected
- nk cells
- oxidative stress
- dendritic cells
- rheumatoid arthritis
- poor prognosis
- rna seq
- autism spectrum disorder
- tyrosine kinase
- mesenchymal stem cells
- chemotherapy induced
- radiation therapy
- long non coding rna
- adipose tissue
- transcription factor
- cell cycle arrest
- metabolic syndrome
- working memory
- neoadjuvant chemotherapy
- lymph node
- protein kinase
- diabetic rats
- peripheral blood
- high throughput
- drug induced
- wild type