Abstract Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes are engulfed primarily by alveolar macrophages (AM), which become reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist Decorin. In untreated recipients, high airway TGF-β activity stimulates AM to express CCL2 leading to CCR2 + monocyte-driven BOS development. Moreover, we find TGF-β receptor 2-dependent differentiation of CCR2 + monocytes is required for the generation of monocyte-derived AM, which in turn promote BOS by expanding tissue-resident memory CD8 + T cells that inflict airway injury through Blimp-1-mediated Granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-β-dependent network, which couples CCR2 + monocyte recruitment and differentiation to alloimmunity and BOS. Alveolar macrophage plasticity can be harnessed to prevent Bronchiolitis Obliterans Syndrome.

Reprogramming Alveolar Macrophage Responses to TGF-β Reveals CCR2+ Monocyte Activity that Promotes Bronchiolitis Obliterans Syndrome