| First Author | Huysentruyt J | Year | 2024 |
| Journal | Cell Death Differ | Volume | 31 |
| Issue | 6 | Pages | 820-832 |
| PubMed ID | 38734851 | Mgi Jnum | J:349806 |
| Mgi Id | MGI:7658831 | Doi | 10.1038/s41418-024-01301-w |
| Citation | Huysentruyt J, et al. (2024) RIPK1 protects naive and regulatory T cells from TNFR1-induced apoptosis. Cell Death Differ 31(6):820-832 |
| abstractText | 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(DeltaCD4)) 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(DeltaCD4) 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(DeltaCD4) 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(DeltaCD4)Casp8 (DeltaCD4) and Ripk1(DeltaCD4)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. |
