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

• Published in: The Journal of clinical investigation Vol. 124; no. 8; pp. 3443 - 3454
• Main Authors: Thornley, Thomas B, Fang, Zemin, Balasubramanian, Savithri, Larocca, Rafael A, Gong, Weihua, Gupta, Shipra, Csizmadia, Eva, Degauque, Nicolas, Kim, Beom Seok, Koulmanda, Maria, Kuchroo, Vijay K, Strom, Terry B
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.08.2014
• Subjects: Allografts; Animals; Antigens; Apoptosis; Biomedical research; Cell Differentiation; Cell Movement; Cell Proliferation; Cell receptors; Diabetes; Flow cytometry; Genotype & phenotype; Graft Survival; Heart; Heart Transplantation; Immune response; Lymphocyte Culture Test, Mixed; Macrophages; Macrophages - cytology; Macrophages - immunology; Macrophages - physiology; Male; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Oxidative Stress; Physiological aspects; Sialic Acid Binding Ig-like Lectin 1 - metabolism; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - physiology; Transplantation Tolerance; Transplants & implants; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI73527

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.