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Although Tregs express a TCR repertoire with relatively high affinities to self, they are normally quite stable, and their inflammatory programs are intrinsically suppressed. We report here that diacylglycerol kinases (DGK) \u03b1 and \u03b6 are crucial for homeostasis, suppression of proinflammatory programs, and stability of Tregs, and for enforcing their dependence on CD28 costimulatory signal. Treg-specific deficiency of both DGK\u03b1 and \u03b6 derails signaling, metabolic, and transcriptional programs in Tregs to cause dysregulated phenotypic and functional properties and to unleash conversion to pathogenic exTregs, especially exTreg-T follicular helper (Tfh) 2 cells, leading to uncontrolled effector T cell differentiation, deregulated germinal center B-cell responses, and IgG1\/IgE predominant antibodies\/autoantibodies, and multiorgan autoimmune diseases. Our data not only illustrate the crucial roles of DGKs in Tregs to maintain self-tolerance, but also unveil a Treg-to-self-reactive-pathogenic-exTreg-Tfh-cell program that is suppressed by DGKs and that could exert broad pathogenic roles in autoimmune diseases if unchecked.<\/jats:p>","DOI":"10.7554\/elife.105212","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T07:25:07Z","timestamp":1739863507000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.105212","source":"Crossref","is-referenced-by-count":2,"title":["DGK\u03b1 and \u03b6 deficiency causes regulatory T-cell dysregulation, destabilization, and conversion to pathogenic T-follicular helper cells to trigger IgG1-predominant 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