Phantom of the immunologic opera: Unmasking the role of innate lymphoid cells (ILC) in inborn errors of immunity (IEI).

Just as the Phantom orchestrates events from the shadows of the Paris Opera House, innate lymphoid cells (ILC) operate behind the scenes of the immune system, shaping immune responses without the antigen specificity of their T cell counterparts. While more understudied than their better-known T cell counterparts, these enigmatic cells serve as first responders to infection and tissue disruption, playing crucial roles in mucosal immunity and homeostasis-packing an iron-fist punch under a velvet glove. However, in the context of inborn errors of immunity (IEI)-a diverse group of over 500 monogenic disorders affecting immune function-the role of ILC remains largely unmasked. While traditionally overlooked, recent patient studies reveal that ILC dysfunction contributes to disease pathogenesis in at least 19 distinct IEI, raising critical questions: Are ILC indispensable protectors, or do they represent a redundant act within the immune repertoire? How do they respond to standard treatments such as hematopoietic stem cell transplantation (HSCT)? In this review, we unveil the hidden roles of ILC in IEI, analyzing their developmental and functional defects, their role in immune dysregulation, and their therapeutic potential. Much like the Phantom's elusive presence, ILC may hold the key to understanding immune resilience and designing novel treatments for immunocompromised patients.