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C5aR1 regulates migration of suppressive myeloid cells required for costimulatory blockade‐induced murine allograft survival
Author(s) -
Llaudo Ines,
Fribourg Miguel,
Medof M. Edward,
Conde Patricia,
Ochando Jordi,
Heeger Peter S.
Publication year - 2019
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15072
Subject(s) - myeloid , immunology , medicine , blockade , cytotoxic t cell , integrin alpha m , peripheral blood mononuclear cell , cancer research , biology , receptor , immune system , in vitro , biochemistry
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.