| First Author | Llaudo I | Year | 2019 |
| Journal | Am J Transplant | Volume | 19 |
| Issue | 3 | Pages | 633-645 |
| PubMed ID | 30106232 | Mgi Jnum | J:280569 |
| Mgi Id | MGI:6369926 | Doi | 10.1111/ajt.15072 |
| Citation | Llaudo I, et al. (2019) C5aR1 regulates migration of suppressive myeloid cells required for costimulatory blockade-induced murine allograft survival. Am J Transplant 19(3):633-645 |
| abstractText | Costimulatory blockade-induced murine cardiac allograft survival requires intragraft accumulation of CD11b(+) Ly6C(lo) Ly6G(-) regulatory myeloid cells (Mregs) that expand regulatory T cells (Tregs) and suppress effector T cells (Teffs). We previously showed that C5a receptor (C5aR1) signaling on T cells activates Teffs and inhibits Tregs, but whether and/or how C5aR1 affects Mregs required for transplant survival is unknown. Although BALB/c hearts survived >60 days in anti-CD154 (MR1)-treated or cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig-treated wild-type (WT) recipients, they were rejected at ~30 days in MR1-treated or CTLA4-Ig-treated recipients selectively deficient in C5aR1 restricted to myeloid cells (C5ar1(fl/fl) xLysM-Cre). This accelerated rejection was associated with ~2-fold more donor-reactive T cells and ~40% less expansion of donor-reactive Tregs. Analysis of graft-infiltrating mononuclear cells on posttransplant day 6 revealed fewer Ly6C(lo) monocytes in C5ar1(fl/fl) xLysM-Cre recipients. Expression profiling of intragraft Ly6C(lo) monocytes showed that C5aR1 deficiency downregulated genes related to migration/locomotion without changes in genes associated with suppressive function. Cotransfer of C5ar1(fl/fl) and C5ar1(fl/fl) xLysM-Cre myeloid cells into MR1-treated allograft recipients resulted in less accumulation of C5ar1(-) (/) (-) cells within the allografts, and in vitro assays confirmed that Ly6C(hi) myeloid cells migrate to C5a/C5aR1-initiated signals. Together, our results newly link myeloid cell-expressed C5aR1 to intragraft accumulation of myeloid cells required for prolongation of heart transplant survival induced by costimulatory blockade. |
