The Autoimmunity-Associated Minor Allele of PTPN22 Accelerates NK Cell Development and Augments Effector Function 2255984

Abstract Introduction Ptpn22 is expressed exclusively in immune cells and shows the highest expression in natural killer (NK) cells, yet its role in NK cells is unknown. Mice expressing the autoimmunity-associated minor allele of Ptpn22, PEP-R619W, have enhanced protection and antiviral immunity during murine coronavirus infection. This protective phenotype is partially driven by augmenting NK cell effector function to restrict viral replication. Due to these findings, we wanted to define the role of Ptpn22 and its PEP-R619W variant in NK cells during development and how they differentially regulate cytokine-mediated activation and cytotoxic function. Methods To investigate the role of Ptpn22 and its variant in NK cell biology, we utilized wild-type (PEP-WT) and CRISPR-Cas9-generated Ptpn22 knockout (PEP-null) and PEP-R619W mice. We assessed the impact of PEP-null and PEP-R619W on NK cell development, maturation, cytokine signaling, and cytotoxic function using flow cytometry. Results In the bone marrow, NK cell numbers were increased, and maturation was accelerated in PEP-null and, more so, in PEP-R619W mice compared to PEP-WT. Mechanistically, Ptpn22 restricts IL-15 signaling, as PEP-null and PEP-R619W NK cells showed enhanced Granzyme B and pro-survival protein expression (Ki67, Bcl-2) following IL-15 stimulation. Furthermore, the addition of IL-15 to IL-12 and IL-18 stimulation elevated IFN-γ production in PEP-R619W NK cells over PEP-WT and PEP-null NK cells. Functionally, PEP-null and PEP-R619W NK cells displayed superior cytotoxicity against tumor targets ex vivo, with the R619W variant again being the most potent. Conclusion Our findings reveal that Ptpn22 is a novel regulator of IL-15 signaling and that its PEP-R619W variant modulates this pathway through additional mechanisms leading to heightened IL-15 responsiveness. This leads to NK cells with augmented effector functions compared to PEP-WT and PEP-null, highlighting the pleiotropic effects of this autoimmune-associated allelic variant. Funding Source NIH Chemical Biology T32 Training Grant GM13206 KU Chemical Biology of Infectious Disease (COBRE) P20GM113117 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)