Previous data from our lab demonstrated that the motheaten mouse strain, which globally lacks SHP-1 due to a splicing mutation (59), carries Treg cells that are hyper-active both in vitro and in vivo (60) However, global loss of SHP-1 causes spontaneous inflammation and autoimmunity at a young age (61); this complicates the ability to discern phenotypes that are cell intrinsic and those emerging from the overall inflammatory environment. The gene discussed is PTPN6; the disease is Autoimmunity.