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bioRxiv · 10.64898/2026.05.12.723629

Rac2 Hyperactivity Drives Neutrophil Degranulation, Myeloperoxidase Deficiency, and Lymphopenia

Hanson, H.·Rodriguez, M.·Kugelmann, E.·Malafei, M.·Boe, M.·Montell, D. J.
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Abstract

Patients with a dominant mutation in the Rho GTPase RAC2, RAC2E62K, which hyperactivates the protein, suffer from a combined immunodeficiency characterized by recurrent bacterial and fungal infections and severe T cell lymphopenia. Patient neutrophils have elevated F-actin and superoxide production yet fail to control growth of S. aureus, and the mechanism underlying this killing defect is unknown. Here we report that hyperactive Rac2 primes neutrophils for primary granule degranulation, potentially depleting myeloperoxidase (MPO) needed for intraphagosomal microbial killing. Using a Rac2+/E62K mouse model, we show that mature bone marrow neutrophils have decreased side scatter, elevated surface CD63, and reduced intracellular MPO. Interestingly, bone marrow architecture and neutrophil development in the mice are normal. Rac2+/E62K neutrophils are hyperactivated, with increased CD11b expression, cell spreading, and bioparticle phagocytosis. In the spleen, Rac2+/E62K mice display extramedullary granulopoiesis and an accumulation of degranulating neutrophils. Splenic T cells, but not B cells, show elevated surface phosphatidylserine, an "eat me" signal that sensitizes them to phagocytic clearance and provides a candidate mechanism for the selective T cell lymphopenia. Together these findings suggest that hyperactive Rac2 compromises antimicrobial neutrophil function and drives selective T cell clearance in the spleen.

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Hanson, H., Rodriguez, M., Kugelmann, E., Malafei, M., Boe, M., Montell, D. J.. 2026-05-15. Rac2 Hyperactivity Drives Neutrophil Degranulation, Myeloperoxidase Deficiency, and Lymphopenia. https://doi.org/10.64898/2026.05.12.723629

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