Differential roles of human CD4+ and CD8+ regulatory T cells in controlling self-reactive immune responses 2723

Abstract Description It has recently emerged that a small subset of CD8+ T cells in humans or mice plays a key role in controlling autoimmunity. However, how these cells function compared to the much better-known CD4+ regulatory T cells is not well understood. Here, we analyzed the relative contribution of CD4 + (FOXP3+) and CD8 + (KIR+) regulatory T cells to the control of autoreactive T and B lymphocytes in human tonsil-derived immune organoids. FOXP3 and GZMB are essential genes in the suppressive functions of CD4+ and CD8+ regulatory T cells, respectively, and we were able to reduce the expression of these genes by ∼90-95% using CRISPR-Cas9 gene editing. Knocking out FOXP3 in tonsil T cells produced antibodies to a variety of autoantigens and also increased the affinity of influenza-specific antibodies. In contrast, a knocking out GZMB resulted in an increase in follicular helper T cells, consistent with the ablation of CD8+ regulatory T cells in mouse models, and a marked increase in autoreactive CD8+ and CD4+ T cells. Thus, CD8+ and CD4+ regulatory T cells have distinct and complementary roles in regulating cellular and humoral responses to prevent autoimmunity. Funding Sources Supported by the Howard Hughes Medical Institute, Open Philanthropy, The Bill and Melinda Gates Foundation, and NIAID (AI057229) Topic Categories Basic Autoimmunity (BA)