Molecular requirements for human lymphopoiesis as defined by inborn errors of immunity.

Hematopoietic stem cells (HSCs) are the progenitor cells that give rise to the diverse repertoire of all immune cells. As they differentiate, HSCs yield a series of cell states that undergo gradual commitment to become mature blood cells. Studies of hematopoiesis in murine models have provided critical insights about the lineage relationships between stem cells, progenitors, and mature cells and these have guided investigations of the molecular basis for these distinct developmental stages. Primary immune deficiencies are caused by inborn errors of immunity that result in immune dysfunction and subsequent susceptibility to severe and recurrent infection(s). Over the last decade there has been a dramatic increase in the number and depth of the molecular, cellular and clinical characterization of such genetically defined causes of immune dysfunction. Patients harboring inborn errors of immunity thus represent a unique resource to improve our understanding of the multi-layered and complex mechanisms underlying lymphocyte development in humans. These breakthrough discoveries not only enable significant advances in the diagnosis of such rare and complex conditions but also provide substantial improvement in the development of personalized treatments. Here, we will discuss the clinical, cellular and molecular phenotypes and treatments of selected inborn errors of immunity that impede, either intrinsically or extrinsically, the development of B- or T-cells at different stages. © AlphaMed Press 2021 SIGNIFICANCE STATEMENT: Hematopoietic stem cells are critical for lifelong production of blood cells. HSCs are distinctively defined by their self-renewal capacity while contributing to the pool of differentiating cells (ie, lymphocytes, neutrophils, and monocytes/macrophages) that ensure immune regulation and protective immunity against pathogen infection. Here, we discuss how the comprehensive study of a growing number of patients harboring rare germline genetic defects that result in immune dysfunctions and increased susceptibility to infectious disease (collectively named primary immunodeficiencies), have enabled a better understanding of the intricate process of lymphocyte development in human, improved diagnosis and facilitated the development of curative rather than supportive treatments for patients with primary immunodeficiencies.