*Purpose: Transmembrane Activator and CAML Interactor (TACI) is a highly polymorphic receptor that controls B cell activation and differentiation into antibody-secreting cells. Allelic variants of TACI have been shown to modulate B cell immune response and may affect outcomes in transplantation in mice and humans.

*Methods: To this end, C57BL/6 mice with mono-allelic and bi-allelic mutations that model disruptive human TNFRSF13B mutations were immunized with BALB/c splenocytes and thymocytes and B cell allo-responses were evaluated. Additionally, DNA was extracted from 286 kidney transplant patients with antibody-mediated rejection (AMR) or with stable graft function and the transmembrane and extracellular domains encoded by exons 3 to 5 of TNFRSF13B were sequenced.

*Results: Tnfrsf13b mice with dominant-negative mutations had decreased levels of natural antibodies and increased activation of complement. Stimulation with allogenic cells of the mutant mice led to enhanced donor-specific antibody affinity maturation and decreased generation of regulatory T cells. Germinal center B cells of mutant mice exhibited decreased expression of genes controlling plasma cell differentiation, immunoglobulin production and immune-regulation. In humans, 30% of the rejecting kidney graft recipients sequenced had missense mutations in exons 3, 4 or 5 compared to 6% of stable allograft group (p<0.0001, Fisher’s exact test). Missense mutations in exons 3 (C104R) and 4 (A173T, A181E, K188del, K188M, R189M, G190R and S209F) were detected in subjects with AMR but never in patients with stable graft function.

*Conclusions: Taken together, these data indicate that common, functionally significant TNFRSF13B polymorphisms could play an important role in determining the outcome of clinical allografts.

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