Myc-Interacting Zinc Finger Protein 1 (Miz-1) Is Essential to Maintain Homeostasis and Immunocompetence of the B Cell Lineage

SIMPLE SUMMARY: The immune system of mice and humans acts against pathogenic threats and intrinsic risks such as cancer. B cells, as antibody-producing cells, provide the ability to specifically target these risks. However, aging leads to a progressive loss of this ability and molecular causes of the gradual loss of immunocompetence remain unknown. Using genetically modified mice, we unravel the transcription factor Miz-1 as a key player of B cell aging during bone marrow lymphopoiesis and peripheral maturation. This enables the investigation of B cell-specific aging mechanisms and how to counteract them for therapeutic approaches to improve immunocompetence in the elderly. ABSTRACT: Aging of the immune system is described as a progressive loss of the ability to respond to immunologic stimuli and is commonly referred to as immunosenescence. B cell immunosenescence is characterized by a decreased differentiation rate in the bone marrow and accumulation of antigen-experienced and age-associated B cells in secondary lymphoid organs (SLOs). A specific deletion of the POZ-domain of the transcription factor Miz-1 in pro-B cells, which is known to be involved in bone marrow hematopoiesis, leads to premature aging of the B cell lineage. In mice, this causes a severe reduction in bone marrow-derived B cells with a drastic decrease from the pre-B cell stage on. Further, mature, naïve cells in SLOs are reduced at an early age, while post-activation-associated subpopulations increase prematurely. We propose that Miz-1 interferes at several key regulatory checkpoints, critical during B cell aging, and counteracts a premature loss of immunocompetence. This enables the use of our mouse model to gain further insights into mechanisms of B cell aging and it can significantly contribute to understand molecular causes of impaired adaptive immune responses to counteract loss of immunocompetence and restore a functional immune response in the elderly.