IRE1α-XBP1 safeguards hematopoietic stem and progenitor cells by restricting pro-leukemogenic gene programs.

Hematopoietic stem cells must mitigate myriad stressors throughout their lifetime to ensure normal blood cell generation. Here, we uncover unfolded protein response stress sensor inositol-requiring enzyme-1α (IRE1α) signaling in hematopoietic stem and progenitor cells (HSPCs) as a safeguard against myeloid leukemogenesis. Activated in part by an NADPH oxidase-2 mechanism, IRE1α-induced X-box binding protein-1 (XBP1) mediated repression of pro-leukemogenic programs exemplified by the Wnt-β-catenin pathway.

Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte β-selection.

Signals from the pre-T cell receptor and Notch coordinately instruct β-selection of CD4CD8double negative (DN) thymocytes to generate αβ T cells in the thymus. However, how these signals ensure a high-fidelity proteome and safeguard the clonal diversification of the pre-selection TCR repertoire given the considerable translational activity imposed by β-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint during β-selection.

Pregnancy promotes tolerance to future offspring by programming selective dysfunction in long-lived maternal T cells.

Fetal antigen available during pregnancy induces the proliferation of maternal T cells. It is unknown, however, whether these antigen-activated T cells differentiate into long-lived memory T cells that are capable of mediating rapid-recall responses to tissue antigens. To test the hypothesis that pregnancy induces an alternative fate in fetal-specific maternal T cells, we used a murine model to track longitudinally fetal-specific T cells in pregnant and postpartum animals and test the response of these cells when challenged with the same antigen during sequential pregnancy or skin transplantation.