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The current review highlights how inborn errors of immunity (IEI) due to IL-2 receptor (IL-2R) subunit defects may result in children presenting with a wide variety of infectious and inflammatory presentations beyond typical X-linked severe combined immune deficiency (X-SCID) associated with IL-2Rγ.Newborn screening has made diagnosis of typical SCID presenting with severe infections less common. Instead, infants are typically diagnosed in the first days of life when they appear healthy. Although earlier diagnosis has improved clinical outcomes for X-SCID, atypical SCID or other IEI not detected on newborn screening may present with more limited infectious presentations and/or profound immune dysregulation. Early management to prevent/control infections and reduce inflammatory complications is important for optimal outcomes of definitive therapies. Hematopoietic stem cell transplant (HSCT) is curative for IL-2Rα, IL-2Rβ, and IL-2Rγ defects, but gene therapy may yield comparable results for X-SCID.Defects in IL-2R subunits present with infectious and inflammatory phenotypes that should raise clinician's concern for IEI. Immunophenotyping may support the suspicion for diagnosis, but ultimately genetic studies will confirm the diagnosis and enable family counseling. Management of infectious and inflammatory complications will determine the success of gene therapy or HSCT.

The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact ofRAG1/RAG2on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an ‘experiment of nature’ to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal aRAG-dependent ‘domino effect’ that impacts stringency of tolerance and B cell fate in the periphery.