Macrophage subpopulations and their impact on chronic allograft rejection versus graft acceptance in a mouse heart transplant model

Abstract

<p class="first" id="P1">Macrophages infiltrating the allografts are heterogeneous, consisting of pro-inflammatory (M1 cells) as well as anti-inflammatory and fibrogenic phenotypes (M2 cells); they affect transplant outcomes via diverse mechanisms. Herein, we found that macrophage polarization into M1 and M2 subsets was critically dependent on TRAF6 and mTOR, respectively. In a heart transplant model we showed that macrophage-specific deletion of TRAF6 (LysM ^Cre <i>Traf6</i> ^fl/fl) or mTOR (LysM ^Cre <i>Mtor</i> ^fl/fl) did not affect acute allograft rejection. However, treatment of LysM ^Cre <i>Mtor</i> ^fl/fl recipients with CTLA4-Ig induced long-term allograft survival (&gt;100 days) without histological signs of chronic rejection, whereas the similarly treated LysM ^Cre <i>Traf6</i> ^fl/fl recipients developed severe transplant vasculopathy (chronic rejection). The presentation of chronic rejection in CTLA4-Ig treated LysM ^Cre <i>Traf6</i> ^fl/fl mice was similar to that of CTLA4-Ig treated wild type B6 recipients. Mechanistically, we found that the graft infiltrating macrophages in LysM ^Cre <i>Mtor</i> ^fl/fl recipients expressed high levels of PD-L1, and PD-L1 blockade readily induced rejection of otherwise survival grafts in the LysM ^Cre <i>Mtor</i> ^fl/fl recipients. Our findings demonstrate that targeting mTOR-dependent M2 cells is critical in preventing chronic allograft rejection and that graft survival under such conditions is dependent on the PD-1/PD-L1 co-inhibitory pathway. </p>