*Purpose: Interleukin-27 (IL-27), a member of IL-12 cytokine family, is involved in both pro- and anti-inflammatory immune responses. Previously we reported that B cell derived IL-27 facilitates reconstitution of CD8 T cells following lymphoablation. The goal of this study was to test the role of IL-27 in alloimmunity and allograft rejection.

*Methods: Full MHC-mismatched heart allografts were transplanted from BALB/c (H-2^d) to naïve B6.WT or B6.IL-27R^-/- mice (H-2^b).

*Results: The absence of recipient IL-27R had no significant impact on graft survival (MST 7d, vs. 8d, for WT and IL27R^-/-, respectively, n=6 mice/group). Furthermore, the frequencies of IFNγ-producing donor-reactive spleen T cells measured by ELISPOT were similar in both groups. However, donor specific antibody (DSA) generation was severely impaired in IL-27R^-/- compared to WT recipients, with 65% and 75% reduction at d. 21 posttransplant for the levels of MHC class I- and class II-reactive DSA, respectively. To identify cell populations producing IL-27 following transplantation, we generated and used B6 IL-27 Tomato Red B6.IL-27^TR reporter mice. We found that both before and after transplantation CD11b⁺CD11c^– (66.7% TR⁺), CD11c⁺CD11b^–CD8⁺ (93.8% TR⁺) and CD11c⁺CD11b^–CD8^– (71.6% TR⁺) cells were the main source of IL-27 at d. 12 posttransplant albeit 43.8% of CD138+ plasma cells also upregulated IL-27 at d. 7 posttransplant. We next tested the expression of IL-27R on various immune cells. Prior to transplantation, IL-27R was expressed on both naïve and memory CD4 and CD8 T cells and on B220⁺IgM^intCD21/35^int follicular B cells. Notably, B220⁺GL7^hiCD38^lo germinal center B cells were IL-27R^lo pretransplant but up-regulated IL-27R expression by d. 7 posttranspant suggesting that IL-27 may directly affect this cell subset in the course of anti-donor humoral immune response

*Conclusions: Our data indicate that IL-27 plays a key role in the generation of donor-specific alloantibodies and may be an attractive therapeutic target to control anti-donor B cell responses and antibody mediated transplant rejection.

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