Recipient CD103+ Classical Dendritic Cells Enhance Acute Rejection in Response to Airway Inflammation after Mouse Lung Transplantation

Abstract

Purpose Airway inflammation after lung transplantation (LTX), resulting from infection, pollution, or aspiration, is an important risk factor for chronic lung allograft dysfunction. Classical dendritic cells (cDCs) link innate immunity and adaptive immunity, and exhibit regional and functional specialization in the lung. CD103+ cDCs reside in the airway epithelium. Their role in lung transplantation (LTX) has not been extensively investigated. We hypothesized that CD103+ cDCs augment adaptive immune responses under conditions of lipopolysaccharide (LPS)-induced airway inflammation inamouse minor alloantigen-mismatched orthotopic LTX model (C57BL/10 [B10] →C57BL/6 [B6] and vice versa). Methods BATF3-/- mice (B6 background), lacking CD103+ cDCs, were used. Three comparisons were made: 1) B10 → 6 vs. B10 → ATF3-/-, 2) B10 →B6 vs. B10 → ATF3-/- with 6 doses of intra-tracheal (i.t.) LPS (5μg in 50μlPBS)on serial postoperative days (POD), 3)B6 → 10 and BATF3-/- → 10 with 8 doses of i.t. LPS on serial PODs. The grafts were assessed on POD 28. Results Acute rejection (ISHLT criteria) did not differ significantly between B10 → 6 and B10 → ATF3-/- without LPS, or between B6 → 10 and BATF3-/- → 10 with LPS. In contrast, with LPS exposure, acute rejection scores were lower in B10àBATF3-/- compared to B10 àB6 (Figure A). Surprisingly, lung cell analysis by flow cytometry showed that monocytes and neutrophils were significantly higher in BATF3-/- recipients than wild-type recipients under repeated airway LPS exposure (Figure B). Conclusion Our data show that recipient, but not donor, CD103+ cDCs contribute to the augmentation of acute rejection after LTx in the setting of ongoing airway inflammation. As CD103+ cDCs can promote immune regulation, they may be an important therapeutic target after LTX. Airway inflammation after lung transplantation (LTX), resulting from infection, pollution, or aspiration, is an important risk factor for chronic lung allograft dysfunction. Classical dendritic cells (cDCs) link innate immunity and adaptive immunity, and exhibit regional and functional specialization in the lung. CD103+ cDCs reside in the airway epithelium. Their role in lung transplantation (LTX) has not been extensively investigated. We hypothesized that CD103+ cDCs augment adaptive immune responses under conditions of lipopolysaccharide (LPS)-induced airway inflammation inamouse minor alloantigen-mismatched orthotopic LTX model (C57BL/10 [B10] →C57BL/6 [B6] and vice versa). BATF3-/- mice (B6 background), lacking CD103+ cDCs, were used. Three comparisons were made: 1) B10 → 6 vs. B10 → ATF3-/-, 2) B10 →B6 vs. B10 → ATF3-/- with 6 doses of intra-tracheal (i.t.) LPS (5μg in 50μlPBS)on serial postoperative days (POD), 3)B6 → 10 and BATF3-/- → 10 with 8 doses of i.t. LPS on serial PODs. The grafts were assessed on POD 28. Acute rejection (ISHLT criteria) did not differ significantly between B10 → 6 and B10 → ATF3-/- without LPS, or between B6 → 10 and BATF3-/- → 10 with LPS. In contrast, with LPS exposure, acute rejection scores were lower in B10àBATF3-/- compared to B10 àB6 (Figure A). Surprisingly, lung cell analysis by flow cytometry showed that monocytes and neutrophils were significantly higher in BATF3-/- recipients than wild-type recipients under repeated airway LPS exposure (Figure B). Our data show that recipient, but not donor, CD103+ cDCs contribute to the augmentation of acute rejection after LTx in the setting of ongoing airway inflammation. As CD103+ cDCs can promote immune regulation, they may be an important therapeutic target after LTX.