DGKα and ζ double-deficiencies (DKO) in Tregs unleashes their proinflammatory programs, alleviates CD28-dependence for their development and homeostasis, and facilitates their conversion to pathogenic exTregs, especially exTreg-Tfh2-cells, causing multiorgan autoimmune diseases, deregulated GC B-cell responses and IgG1/IgE predominant autoantibodies, and lupus-like diseases. The gene discussed is CD28; the disease is autoimmune disease.