Very low-dose tolerance with nucleosomal peptides controls lupus and induces potent regulatory T cell subsets

We induced very low-dose tolerance by injecting lupus prone (SWR × NZB)F₁ (SNF1) mice with 1 μg nucleosomal histone peptide autoepitopes s.c. every 2 wk. The subnanomolar peptide therapy diminished autoantibody levels and prolonged life span by delaying nephritis, especially by reducing inflammatory cell reaction and infiltration in kidneys. H4 _71-94 was the most effective autoepitope. Low-dose tolerance therapy induced CD8⁺, as well as CD4⁺CD25⁺ regulatory T (T_reg) cell subsets containing autoantigen-specific cells. These adaptive T_reg cells suppressed IFN-γ responses of pathogenic lupus T cells to nucleosomal epitopes at up to a 1:100 ratio and reduced autoantibody production up to 90-100% by inhibiting nucleosome-stimulated T cell help to nuclear autoantigen-specific B cells. Both CD4⁺CD25 ⁺ and CD8⁺ T_reg cells produced and required TGF-β1 for immunosuppression, and were effective in suppressing lupus autoimmunity upon adoptive transfer in vivo. The CD4⁺CD25⁺ T cells were partially cell contact dependent, but CD8⁺ T cells were contact independent. Thus, low-dose tolerance with highly conserved histone autoepitopes repairs a regulatory defect in systemic lupus erythematosus by generating long-lasting, TGF-β-producing T_reg cells, without causing allergic/anaphylactic reactions or generalized immunosuppression.