Macrophages Join the FOXP3 Suppressor Gang

RESEARCH HIGHLIGHTS

IMMUNE REGULATION Macrophages join the FOXP3 suppressor gang

The transcription factor forkhead What is the function of these cells in established B16 melanoma box P3 (FOXP3) has been used cells? Freshly isolated FOXP3+ tumours were found to be FOXP3+ for several years to identify regula- macrophages were found to inhibit macrophages. However, analysis at + tory T cells (TReg cells). Now, a new CD4 T cell proliferation in vitro. earlier time points showed that when study published in The Journal of Small interfering RNA-mediated tumour volume was low (day 10), Experimental Medicine shows that knockdown of FOXP3 expression the number of FOXP3+ macrophages the expression of FOXP3 by immune in FOXP3+ macrophages abrogated was higher than the number of + cells is not restricted to TReg cells their ability to inhibit T cell prolifera- FOXP3 TReg cells, suggesting that and that FOXP3+ macrophages have tion, indicating that FOXP3 directly these regulatory macrophages may suppressive functions and promote confers suppressive functions to have a role early in tumour develop- tumour growth. these cells. Further analyses showed ment. To examine this further, + + While evaluating FOXP3 TReg that the suppressive capacity of the authors transferred FOXP3 or cells in mice, the authors observed a FOXP3+ macrophages was medi- FOXP3– macrophages with tumour population of FOXP3+ cells that were ated by the production of a soluble cells to F4/80- or CD11b‑deficient also CD11b+. These cells were found factor and not through cell–cell mice (both strains do not develop to express other macrophage markers, contact; this factor was identified as tumours following tumour cell such as F4/80 and CD68, and could prostaglandin E2. transfer). A low level of tumour be detected in the bone marrow, Next, the authors sought to growth was observed in mice that thymus, spleen, lymph nodes and determine whether FOXP3– macro received tumour cells mixed with liver of wild-type mice. These cells phages could be induced to express FOXP3– macrophages; however, had macrophage morphology and a FOXP3 in a similar manner to in mice that received FOXP3+

phagocytic capacity that was similar to induced TReg cells. They found that macrophages, tumours developed F4/80+FOXP3– macrophages, indicat- stimulation of FOXP3– macrophages at almost the same rate as in control ing that these CD11b+F4/80+FOXP3+ with various factors — including wild-type mice. Furthermore, cells are of macrophage origin. LPS, CpG DNA, TGFβ and VEGF — transferring FOXP3+ macrophages for 3 days induced the conversion together with a small number of of some of these cells to FOXP3+ tumour cells that do not usually macrophages that had a phenotype cause tumour development in and suppressive function indistin- wild-type mice resulted in tumour guishable from naturally occurring growth. These studies suggest that FOXP3+ macrophages. FOXP3+ macrophages can support Global transcriptional and and promote tumour growth. protein production analyses In summary, this study describes were carried out on FOXP3+ and a unique population of naturally FOXP3– macrophages, and the occurring regulatory macrophages results showed that the cytokine, that express FOXP3, can suppress chemokine and growth factor T cell proliferation and promote expression profiles were different tumour growth. between these two cell subsets, Olive Leavy suggesting that these cells have ORIGINAL RESEARCH PAPER Zorro Manrique, S. distinct biological functions. et al. Foxp3‑positive macrophages display But do these regulatory immunosuppressive properties and promote macrophages have a role in vivo? tumor growth. J. Exp. Med. 13 Jun 2011 (doi:10.1084/jem.20100730) A small percentage of CD11b+