Lymph nodes stromal cells (LNSCs) modulate the functions of hematopoietic antigen-presenting cells (APCs) and impact T cell homeostasis. LNSCs can ectopically express peripheral tissue-restricted antigens and present them through MHCI to induce self-reactive CD8+ T cell deletion. To study their role as MHCII-restricted APCs, we used a mouse model where MHCII was abrogated in LNSCs. Aging mice developed spontaneous autoimmunity, including enhanced T cell activation, autoantibodies, and T cell infiltration in peripheral organs. Our data highlight a tolerogenic impact of MHCII-mediated self-antigen presentation by LNSCs on CD4+ T cells in autoimmunity. However, mechanisms of immune suppression can lead to pathogens or tumors escaping immune responses. A second axis of our investigations was to determine whether tumor associated LNSCs present tumor antigens through MHCII and modulate tumor specific CD4+ T cell responses. Our preliminary data indicate that tumor associated LNSCs support immunosuppression, promote tumor growth and that MHCII-tumor antigen presentation has pro-tumoral functions. Our project revealed crucial new insights about a role of antigen-presenting LNSCs in peripheral T cell tolerance, a concept that will significantly impacts strategies to modulate their function in cancer and autoimmunity.