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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 Article has an altmetric score of 17

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 5

Graft mono-DCs present antigen to CD4 and CD8 T cells ex vivo.

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Graft mono-DCs present antigen to CD4 and CD8 T cells ex vivo.
(A) T cel...
(A) T cell proliferation (dilution of CTV) and IFN-γ production in response to control splenic CD11b+ DCs sorted from naive mice and fed LPS-free OVA in the presence or absence of exogenous LPS. (B) T cell proliferation and IFN-γ production in response to graft mono-DCs fed LPS-free OVA in the absence of exogenous LPS. Mono-DCs were sorted from syngeneic heart grafts on day 3 after transplantation and from heart allografts on either day 3 or day 42. Same donor-recipient strain combination as in Figure 2, A–C. Flow cytometry was performed 5 days after in vitro stimulation of T cells with DCs. DC/T cell ratio = 1:50. Percentages indicate CFSE-diluted cells. *P < 0.05 compared with the syngeneic group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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