Hypomorphic Rag1 mutations alter the pre-immune repertoire at early stages of lymphoid development

Hypomorphic RAG1 mutations allowing residual T and B cell development have been found in patients presenting with delayed-onset combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI) and abnormalities of the peripheral T and B cell repertoire. In order to examine how hypomorphic Rag1 mutations affect the earliest stages of lymphocyte development, we generated mouse models with equivalent mutations found in patients with CID-G/AI. We identified skewing of Igh V gene segment usage in early progenitors, with a bias for productive Igh rearrangements after selection. Along with similar T cell characterizations, this study provides novel insights in how hypomorphic Rag1 mutations alter the primary repertoire of T and B cells, setting the stage for immune dysregulation frequently seen in patients.