Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 124, Issue 8, Pages 3443-3454Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI73527
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Funding
- National Institute of Allergy and Infectious Disease [5P01A1073748]
- Juvenile Diabetes Research Foundation [3-2010-792]
- National Institute of Diabetes and Digestive and Kidney Diseases [5R01DK096138]
- National Heart, Lung, and Blood Institute [T32HL007893]
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Macrophages characterized as M2 and M2-like regulate immune responses associated with immune suppression and healing; however, the relationship of this macrophage subset to CD169(+) tissue-resident macrophages and their contribution to shaping alloimmune responses is unknown. Here we identified a population of M2-like tissue-resident macrophages that express high levels of the phosphatidylserine receptor TIM-4 and CD169 (TIM-4(hi)CD169(+)). Labeling and tracking of TIM-4(hi)CD169(+) macrophages in mice revealed that this population is a major subset of tissue-resident macrophages, homes to draining LNs following oxidative stress, exhibits an immunoregulatory and hypostimulatory phenotype that is maintained after migration to secondary lymphoid organs, favors preferential induction of antigen-stimulated Tregs, and is highly susceptible to apoptosis. Moreover, CD169(+) tissue-resident macrophages were resistant to oxidative stress-induced apoptosis in mice lacking TIM-4. Compared with heart allografts from WT mice, Tim4(-/-) heart allografts survived much longer and were more easily tolerized by non-immunosuppressed recipients. Furthermore, Tim(4-/-) allograft survival was associated with the infiltration of Tregs into the graft. Together, our data provide evidence that M2-like TIM-4(hi)CD169(+)tissue-resident macrophages are immunoregulatory and promote engraftment of cardiac allografts, but their influence is diminished by TIM-4-dependent programmed cell death.
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