The CD40-CD154 costimulatory axis serves as a central hub bridging innate and adaptive immunity, regulating antigen presentation, T-cell priming, B-cell activation, germinal center formation, and antibody class switching. In transplantation, this pathway drives donor-reactive T-cell expansion, dendritic cell (DC) licensing, and donor-specific antibody generation, contributing to both acute and chronic allograft rejection. Recent discoveries have expanded the classical linear model into a multidimensional signaling network. This network encompasses canonical CD40-TNF receptor-associated factor (TRAF)-NF-κB signaling, CD154 reverse signaling, and alternative receptor engagement—particularly through integrins such as CD11b. These insights explain the differential efficacy of CD154 versus CD40 blockade and inform next-generation therapeutic design. Concurrently, renewed clinical interest has emerged following the development of fragment crystallizable (Fc)-engineered anti-CD154 antibodies that circumvent first-generation thromboembolic toxicity. Here, we synthesize current understanding of CD40-CD154 molecular architecture, upstream triggers, downstream signaling networks, crosstalk with other immune pathways, and cell type-specific outputs. We evaluate therapeutic candidates in clinical development, discuss unresolved questions regarding long-term safety and biomarker development, and highlight future directions including cell-targeted intervention and tolerance-inducing combination strategies.
Wang et al. (2026) studied this question.