DGKα and ζ deficiency causes regulatory T-cell dysregulation, destabilization, and conversion to pathogenic T-follicular helper cells to trigger IgG1-predominant autoimmunity.

Regulatory T cells (Tregs) actively engage in immune suppression to prevent autoimmune diseases, but also inhibit anti-tumor immunity. 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) α and ζ 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 DGKα and ζ 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.