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Non-self recognition by monocytes initiates allograft rejection
Martin H. Oberbarnscheidt, … , David M. Rothstein, Fadi G. Lakkis
Martin H. Oberbarnscheidt, … , David M. Rothstein, Fadi G. Lakkis
Published July 1, 2014
Citation Information: J Clin Invest. 2014;124(8):3579-3589. https://doi.org/10.1172/JCI74370.
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Research Article

Non-self recognition by monocytes initiates allograft rejection

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Abstract

Maturation of T cell–activating APCs directly links innate and adaptive immunity and is typically triggered by microbial infection. Transplantation of allografts, which are sterile, generates strong T cell responses; however, it is unclear how grafts induce APC maturation in the absence of microbial-derived signals. A widely accepted hypothesis is that dying cells in the graft release “danger” molecules that induce APC maturation and initiate the adaptive alloimmune response. Here, we demonstrated that danger signals associated with dying cells are not sufficient to initiate alloimmunity, but that recognition of allogeneic non-self by the innate immune system is required. In WT as well as in T cell–, B cell–, and innate lymphoid cell–deficient mice, allogeneic grafts elicited persistent differentiation of monocytes into mature DCs that expressed IL-12 and stimulated T cell proliferation and IFN-γ production. In contrast, syngeneic grafts in the same mice elicited transient and less pronounced differentiation of monocytes into DCs, which neither expressed IL-12 nor stimulated IFN-γ production. In a model in which T cell recognition is restricted to a single foreign antigen on the graft, rejection occurred only if the allogeneic non-self signal was also sensed by the host’s innate immune system. These findings underscore the importance of innate recognition of allogeneic non-self by monocytes in initiating graft rejection.

Authors

Martin H. Oberbarnscheidt, Qiang Zeng, Qi Li, Hehua Dai, Amanda L. Williams, Warren D. Shlomchik, David M. Rothstein, Fadi G. Lakkis

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Figure 1

Analysis of myeloid cell infiltrate in heart grafts transplanted into immunocompetent recipients.

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Analysis of myeloid cell infiltrate in heart grafts transplanted into im...
B6 (syngeneic) or BALB/c (allogeneic) CD45.2 heart grafts were transplanted into B6 CX3CR1gfp/+ CD45.1 recipients, except where indicated. Infiltrating cells were analyzed by flow cytometry 1 day after transplantation; n = 4 grafts/group. (A) Representative flow plot depicting lineage– (CD19–CD90–NK1.1–DX5–) recipient (CD45.1+) and donor (CD45.2+) myeloid cells present in syngeneic (Syn) and allogeneic (Allo) grafts. (B) Enumeration of recipient myeloid populations in syngeneic (black bars) and allogeneic (white bars) grafts. Cell surface markers used to identify cell populations are shown in the text box and in the gating strategy in Supplemental Figure 1. N, neutrophils; Mono, monocytes; DC, dendritic cells; Mϕ, macrophages. (C) Enumeration and representative flow plot of monocyte subsets (Inf, inflammatory Ly-6ChiCX3CR1lo; Pat, patrolling Ly-6CloCX3CR1hi) in syngeneic (black circles represent black events) and allogeneic (white circles represent gray events) grafts. (D) Representative flow plot depicting phenotype of recipient-derived DCs in an allogeneic graft. (E) Enumeration of mature (CD80+) mono-DCs in syngeneic (black circles) and allogeneic (white circles) grafts. Each data point represents 1 graft. Donor-recipient strain combination is indicated on the x axis. *P < 0.05.

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