Sin3A Controls FoxP3+ Treg Production, Stability and Function

Abstract Purpose: Foxp3 T-regulatory (Treg) cells are key to immune homeostasis but the function of paired amphipathic helix protein, Sin3a, is unknown. Methods: We studied effects Sin3a deletion in Treg cells. Results: Sin3a−/− FoxP3Cre mice died from severe autoimmunity by 2–3 weeks birth. Mice had enlarged lymph nodes, inflammation lungs, skin, livers and kidneys autoantibodies islet cells, striated muscles, keratin, endomysium gastric parietal Percentages FoxP3+ Tregs LNs spleens were lower (p values ranging >0.01 >0.0001) than controls FoxP3 mRNA expression (>20-fold) protein per (>3-fold) also significantly reduced mice. Reduction periphery FoxP3cre was largely due loss FoxP3, determined an increase peripheral ex-Tregs as compared WT (p<0.001 sLN spleens) within tdTomatoROSA26 lineage tracing Increased pro-apoptotic genes, decreased anti-apoptotic increased presence Annexin V on cell surface indicate that apoptosis contributed reduction. produced amounts granzyme B, IFN-γ IL-2 (12–45% cells) impaired suppressive (p<0.01). essential for iTreg conversion since CD4+CD25− lacked ability convert iTregs ex vivo. Conclusions: The nuclear co-regulator, helps maintain unique homeostatic properties Therapeutic modulation functions may be possible pharmacologic targeting components complex.