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J Clin Invest. 2014 Aug;124(8):3443-54. doi: 10.1172/JCI73527. Epub 2014 Jul 1.

Fragile TIM-4-expressing tissue resident macrophages are migratory and immunoregulatory.


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-4hiCD169+). Labeling and tracking of TIM-4hiCD169+ 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, Tim4-/- allograft survival was associated with the infiltration of Tregs into the graft. Together, our data provide evidence that M2-like TIM-4hiCD169+ 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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