*Purpose: Extended criteria lung donors are being increasingly utilized, raising the possibility of transplanting lungs with a pre-existing pneumonia; how donor pneumonia alters alloimmune responses, however, is not well understood. We recently uncovered the critical role of recipient-derived monocytes in mediating ischemia-reperfusion injury in a mouse lung transplant model. Here, we test the hypothesis that recipient-derived monocytes activated by Toll-like receptor 2 (TLR2) agonist Pam3Cys4, a synthetic bacterial lipopeptide, can alter alloimmune responses following lung transplantation.

*Methods: Lungs from Balb/c wild type (WT) or Balb/c MyD88 KO were transplanted into B6 WT or B6 TLR2 KO recipients under perioperative co-stimulatory blockade (anti-CD40L at day 0 and CTLA4-Ig at day 2). Pam3Cys4 (50μg) or vehicle were administered into the donor bronchus prior to airway anastomosis in all transplants. For adoptive transfer experiments, T cells or monocytes were isolated from B6 WT mice and intravenously injected into recipient mice just after reperfusion. Lung grafts were harvested on day 7 and evaluated with histology and flow cytometry.

*Results: Balb/c WT lung grafts treated with vehicle and transplanted in B6 WT did not show rejection (Grade A0-A1, n=4). When treated with Pam3Cys4, Balb/c WT and Balb/c MyD88 KO lung grafts transplanted into B6 WT mice developed acute cellular rejection (Grade≥A2, n=4-5/group); however, Balb/c WT lung grafts transplanted in B6 TLR2 KO mice were not rejected (Grade A0-A1, n=5/group) (Figure 1). Rejection was associated with increased abundance of interstitial macrophages, lower CD4/CD8 ratio, and increased expression of Ki67 in CD8+ T cells (p<0.05) within the lung grafts. Adoptive transfer of B6 WT monocytes, but not T cells, following Balb/c WT→B6 TLR2 KO transplants triggered acute cellular rejection (Grade≥A2, n=4).

*Conclusions: Activation of TLR2 by a bacterial lipopeptide present within the donor airway prevents the induction of lung allograft tolerance through a process mediated by recipient-derived monocytes. Our work suggests that donor lungs harboring pneumonia may precipitate an inflammatory response and facilitate allograft rejection.

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