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 among 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 multilayered 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. Patients with inborn errors of immunity represent a unique resource for the deep characterization of the human immune system. The study of these patients revealed essential and redundant requirements for the multilayered and complex mechanisms involved in not only protective immunity but also fundamental processes of immune cell development (lymphopoiesis). Our improved understanding of B‐ and T‐cell differentiation has enabled the development and implementation of curative targeted therapies for inborn errors of immunity.