title: Fragile TIM-4-expressing tissue resident macrophages are migratory and immunoregulatory.
abstract: 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.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Thornley
authors.forename: Zemin
authors.initials: Z
authors.lastname: Fang
authors.forename: Savithri
authors.initials: S
authors.lastname: Balasubramanian
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Larocca
authors.forename: Weihua
authors.initials: W
authors.lastname: Gong
authors.forename: Shipra
authors.initials: S
authors.lastname: Gupta
authors.forename: Eva
authors.initials: E
authors.lastname: Csizmadia
authors.forename: Nicolas
authors.initials: N
authors.lastname: Degauque
authors.forename: Beom Seok
authors.initials: BS
authors.lastname: Kim
authors.forename: Maria
authors.initials: M
authors.lastname: Koulmanda
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
mesh_terms: D064591:Allografts; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D006085:Graft Survival; D016027:Heart Transplantation; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018384:Oxidative Stress; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000502:physiology; D023001:Transplantation Tolerance
chemical_list: D008565:Membrane Proteins; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse; C500399:TIM-4 protein, mouse