01773nas a2200241   4500000000100000000000100001008004100002260001500043653001700058653002100075100001300096700002200109700002400131700001400155700001900169700002300188700001800211245011100229856005500340300000900395520111300404022001401517       2025                            d  c2025-01-1310aAutoimmunity10aImmune tolerance1 aXin Chen1 aMustafa Ghanizada1 aVamsee Mallajosyula1 aElsa Sola1 aRobson Capasso1 aKaran Raj Kathuria1 aMark M. Davis00aDifferential roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses  uhttps://www.nature.com/articles/s41590-024-02062-x  a1-103 aHere we analyzed the relative contributions of CD4+ regulatory T cells expressing Forkhead box protein P3 (FOXP3) and CD8+ regulatory T cells expressing killer cell immunoglobulin-like receptors to the control of autoreactive T and B lymphocytes in human tonsil-derived immune organoids. FOXP3 and GZMB respectively encode proteins FOXP3 and granzyme B, which are critical to the suppressive functions of CD4+ and CD8+ regulatory T cells. Using CRISPR–Cas9 gene editing, we were able to achieve a reduction of ~90–95% in the expression of these genes. FOXP3 knockout in tonsil T cells led to production of antibodies against a variety of autoantigens and increased the affinity of influenza-specific antibodies. By contrast, GZMB knockout resulted in an increase in follicular helper T cells, consistent with the ablation of CD8+ regulatory T cells observed in mouse models, and a marked expansion of autoreactive CD8+ and CD4+ T cells. These findings highlight the distinct yet complementary roles of CD8+ and CD4+ regulatory T cells in regulating cellular and humoral responses to prevent autoimmunity.  a1529-2916