Inhibition of mitochondrial ROS by TACI sustains bone marrow plasma cells

Vaccines establish humoral protection via neutralizing antibodies, which are sustained by bone marrow long-lived plasma cells (LLPC). The lifespan of LLPCs determines the duration of protection, however, the mechanisms underlying LLPC survival remain poorly understood. Here, we employ plasma cell–specific conditional knockout mice to systematically dissect the roles of receptors for candidate niche factors. Unexpectedly, we find that the cytokine receptor TACI is essential for LLPC survival. Loss of TACI reduces polyclonal plasma cell numbers and abrogated LLPCs induced by both T cell-dependent and T cell-independent antigens. Importantly, TACI deficiency severely compromises protection elicited by both SARS-CoV-2 and influenza vaccines. Mechanistically, loss of TACI causes accumulation of mitochondrial reactive oxygen species and subsequent plasma cell death. Importantly, pharmacologic antioxidant treatment with the FDA-approved drug, N‑acetylcysteine, mitigates ROS accumulation, rescues LLPC numbers, and enhances influenza vaccine efficacy in vivo. Together, these results establish TACI as a non-redundant regulator of LLPC longevity and vaccine-induced protection by limiting oxidative stress, providing a potential target for enhancing vaccine efficacy and durability. Long-lived plasma cells (LLPC) in the bone marrow are indispensable for longer-term protection against infections following vaccination. Here the authors show that the cytokine receptor TACI, but not BCMA or BAFFR, protects LLPCs from oxidative stress and thus facilitates their survival, and that genomic deletion of TACI specifically in plasma cells results in reduced numbers of LLCs and reduced vaccine efficacy in mice, which could be mitigated a pharmacologic antioxidant.