Human CD21^loT-bet⁺ B cells: Not as easy as "ABC"!

B cells contribute to many facets of adaptive immunity, including key roles as Ag-presenting cells, cytokine-producing cells, and plasma cells secreting protective antibodies. However, B cell functional dysregulation can result in myriad immune dyscrasias, such as immunodeficiency, chronic infection, autoimmunity, allergy, and malignancy. Thus, it is critical to understand fundamental aspects of human B cell differentiation and effector function. A B cell subset that has attracted much attention over the past 2 decades is a population known by many identities-CD21^lo, atypical memory, CD27^negIgD^neg, age-associated, exhausted-and associated with many diseases, especially humoral immune dysregulation. However, these cells likely also contribute to humoral immunity in the setting of vaccination and natural infection. This Review tries to provide an overview of the discoveries, origins, and complexities of CD21^lo B cells, and how studying inborn errors of immunity can provide a unique window to understand the molecular requirements for generating these cells, as well as mechanisms underpinning function in health and disease.