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Durable humoral immunity against epidemic infectious disease requires the survival of long-lived plasma cells (LLPCs). LLPC longevity is dependent on metabolic programs distinct from short-lived plasma cells (SLPCs); however, the mechanistic basis for this difference is unclear. We have previously shown that CD28, the prototypic T cell costimulatory receptor, is expressed on both LLPCs and SLPCs but is essential only for LLPC survival. Here we show that CD28 transduces pro-survival signaling specifically in LLPCs through differential SLP76 expression. CD28 signaling in LLPCs increased glucose uptake, mitochondrial mass/respiration, and reactive oxygen species (ROS) production. Unexpectedly, CD28-mediated regulation of mitochondrial respiration, NF-κB activation, and survival was ROS dependent. IRF4, a target of NF-κB, was upregulated by CD28 activation in LLPCs and decreased IRF4 levels correlated with decreased glucose uptake, mitochondrial mass, ROS, and CD28-mediated survival. Altogether, these data demonstrate that CD28 signaling induces a ROS-dependent metabolic program required for LLPC survival.
The RNA binding protein ARS2 is highly expressed in hematopoietic progenitor populations and is required for adult hematopoiesis. Recent molecular studies found that ARS2 coordinates interactions between nascent RNA polymerase II transcripts and downstream RNA processing machineries, yet how such interactions influence hematopoiesis remains largely unknown. Techniques to differentiate embryonic stem cells (ESC) to hematopoietic progenitor cells (HPC) and mature blood cells have increased molecular understanding of hematopoiesis. Taking such an in vitro approach to examine the influence of ARS2 on hematopoiesis, we found that ARS2 suppresses expression of some HSC signature genes and differentiation of ESC to a HPC population (CSMD-HPC) identified by markers expressed on bone marrow resident hematopoietic stem cells. In line with ARS2's ability to promote proliferation of cultured cells, ARS2 knockout ESC showed limited expansion and yielded less CSMD-HPC than wild-type ESC. In contrast, transient ARS2 knockdown led to doubling the number of CSMD-HPC generated per ESC without affecting further differentiation into mature T-cells. Overall, data indicate that ARS2 negatively regulates early hematopoietic differentiation of ESC, in stark contrast to its supportive role in adult hematopoiesis. Consequently, manipulation of ARS2 expression and/or function has potential utility in hematopoietic cell engineering and regenerative medicine.
Humoral immunity is essential for protection against pathogens, emphasized by the prevention of 2-3 million deaths worldwide annually by childhood immunizations. Long-term protective immunity is dependent on the continual production of neutralizing antibodies by the subset of long-lived plasma cells (LLPCs). LLPCs are not intrinsically long-lived, but require interaction with LLPC niche stromal cells for survival. However, it remains unclear which and how these interactions sustain LLPC survival and long-term humoral immunity. We now have found that the immunosuppressive enzyme indoleamine 2,3- dioxygenase 1 (IDO1) is required to sustain antibody responses and LLPC survival. Activation of IDO1 occurs upon the engagement of CD80/CD86 on the niche dendritic cells by CD28 on LLPC. Kynurenine, the product of IDO1 catabolism, activates the aryl hydrocarbon receptor in LLPC, reinforcing CD28 expression and survival signaling. These findings expand the immune function of IDO1 and uncover a novel pathway for sustaining LLPC survival and humoral immunity.
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS cases are caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to disease remains unclear. Here, we demonstrate that UBQLN2 regulates the domesticated gag-pol retrotransposon 'paternally expressed gene 10 (PEG10)' in human cells and tissues. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated 'nucleocapsid' fragment, which uniquely localizes to the nucleus and changes the expression of genes involved in axon remodeling. In spinal cord tissue from ALS patients, PEG10 gag-pol is elevated compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through the regulation of gene expression, and restraint of PEG10 as a primary function of UBQLN2.
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