Humoral immunity is essential for protection against pathogens, emphasized by the prevention of 2–3 million deaths worldwide annually by childhood immunizations. Long-term protective immunity is dependent on the continual production of neutralizing antibodies by the subset of long-lived plasma cells (LLPCs). LLPCs are not intrinsically long-lived, but require interaction with LLPC niche stromal cells for survival. However, it remains unclear which and how these interactions sustain LLPC survival and long-term humoral immunity. We now have found that the immunosuppressive enzyme indoleamine 2,3- dioxygenase 1 (IDO1) is required to sustain antibody responses and LLPC survival. Activation of IDO1 occurs upon the engagement of CD80/CD86 on the niche dendritic cells by CD28 on LLPC. Kynurenine, the product of IDO1 catabolism, activates the aryl hydrocarbon receptor in LLPC, reinforcing CD28 expression and survival signaling. These findings expand the immune function of IDO1 and uncover a novel pathway for sustaining LLPC survival and humoral immunity. [Display omitted] • Long-lived plasma cells (LLPCs) are essential for durable antibody (Ab) titers • The pro-survival interactions that maintain LLPC populations remain unclear • DCs in the LLPC niche are essential for LLPC survival and sustained Ab titers • DC-produced indoleamine 2,3-dioxygenase 1 sustains LLPC survival and Ab titers Sustained protective antibody titers following infection/vaccination are produced by long-lived plasma cells (LLPCs). What keeps LLPCs alive remains largely unknown. Lightman et al. have found unexpected involvement of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1, produced by dendritic cells in the LLPC nice, in sustaining LLPC survival and long-term antibody titers. [ABSTRACT FROM AUTHOR]