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ARTICLE RETRACTED: Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth.
J Exp Med. 2011 Jul 4; 208(7):1485-99
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27 Jun 2011
Arthur Hurwitz
F1000 Immunology
Frederick National Laboratory for Cancer Research, National Institutes of Health (NIH),
Frederick, MD, USA.
F1000 Immunology
Frederick National Laboratory for Cancer Research, National Institutes of Health (NIH),
Frederick, MD, USA.
Controversial, New Finding, Novel Drug Target
DOI: 10.3410/f.11565956.12620054
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
Forkhead box p3 (Foxp3) -- it's not just for T cells anymore. This study identifies...Continue reading
Forkhead box p3 (Foxp3) -- it's not just for T cells anymore. This study identifies...Continue reading
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
Forkhead box p3 (Foxp3) -- it's not just for T cells anymore. This study identifies a sub-population of macrophages, present in all lymphoid tissues, which express the transcription factor Foxp3. These macrophages suppress T cell responses in a prostaglandin E2 (PGE2)-dependent manner and promote tumor growth. This is a new criterion for identifying immunosuppressive macrophages.
The identification of this subset of macrophages may provide a novel avenue for therapeutic intervention for cancer immunotherapy, infectious diseases, or immune-based therapy for autoimmune disease.
Forkhead box p3 (Foxp3) -- it's not just for T cells anymore. This study identifies a sub-population of macrophages, present in all lymphoid tissues, which express the transcription factor Foxp3. These macrophages suppress T cell responses in a prostaglandin E2 (PGE2)-dependent manner and promote tumor growth. This is a new criterion for identifying immunosuppressive macrophages.
The identification of this subset of macrophages may provide a novel avenue for therapeutic intervention for cancer immunotherapy, infectious diseases, or immune-based therapy for autoimmune disease.
Disclosures
None declared
Add Comment
Hurwitz A: F1000Prime Recommendation of [Manrique SZ et al., J Exp Med 2011, 208(7):1485-99]. In F1000Prime, 27 Jun 2011; DOI: 10.3410/f.11565956.12620054. F1000Prime.com/11565956#eval12620054
07 Jul 2011
New Finding
DOI: 10.3410/f.11565956.12851055
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
The study by Zorro Manrique et al. is important because it challenges the existing...Continue reading
The study by Zorro Manrique et al. is important because it challenges the existing...Continue reading
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
The study by Zorro Manrique et al. is important because it challenges the existing dogma of a functional distinction between regulatory T cells and macrophages.
Classically activated macrophages and the proinflammatory cytokines they secrete have long been associated with the pathologies that occur in a number of autoimmune diseases. The job of regulating immune responses has traditionally been assigned to T cells. Now, however, our perception of immunoregulation is beginning to change. In the present study the authors identified macrophages expressing FOXp3 and demonstrated that they have potent immunoregulatory activity. This observation takes immunoregulation to another level of complexity, blurring the lines of distinction between regulatory T cells (Tregs) and macrophages.
In this work the authors demonstrate that a subset of Foxp3 monocytes and macrophages are found in many different organs. These cells are phagocytic, express macrophage markers, and are found in normal numbers in T cell-deficient mice, indicating that they are clearly distinct from Tregs. When, added to T cells these regulatory macrophages were potent suppressors of T cell proliferation. They also promote tumor growth in vivo. Similar to Tregs, both naturally occurring and induced regulatory macrophages exist, and while regulatory macrophages induce many genes in common with Tregs, the mechanism of suppression appears to be unique to macrophages and may depend on the production of prostaglandin E2 (PGE2). We can certainly look forward to additional studies to determine whether human Foxp3 macrophages exist and have a similar immunosuppressive activity. In conclusion, this paper is highly significant because it opens up new avenues of investigation into a novel macrophage subpopulation which will have important implications for the design of novel immunotherapeutics for cancer and perhaps autoimmune diseases.
The study by Zorro Manrique et al. is important because it challenges the existing dogma of a functional distinction between regulatory T cells and macrophages.
Classically activated macrophages and the proinflammatory cytokines they secrete have long been associated with the pathologies that occur in a number of autoimmune diseases. The job of regulating immune responses has traditionally been assigned to T cells. Now, however, our perception of immunoregulation is beginning to change. In the present study the authors identified macrophages expressing FOXp3 and demonstrated that they have potent immunoregulatory activity. This observation takes immunoregulation to another level of complexity, blurring the lines of distinction between regulatory T cells (Tregs) and macrophages.
In this work the authors demonstrate that a subset of Foxp3 monocytes and macrophages are found in many different organs. These cells are phagocytic, express macrophage markers, and are found in normal numbers in T cell-deficient mice, indicating that they are clearly distinct from Tregs. When, added to T cells these regulatory macrophages were potent suppressors of T cell proliferation. They also promote tumor growth in vivo. Similar to Tregs, both naturally occurring and induced regulatory macrophages exist, and while regulatory macrophages induce many genes in common with Tregs, the mechanism of suppression appears to be unique to macrophages and may depend on the production of prostaglandin E2 (PGE2). We can certainly look forward to additional studies to determine whether human Foxp3 macrophages exist and have a similar immunosuppressive activity. In conclusion, this paper is highly significant because it opens up new avenues of investigation into a novel macrophage subpopulation which will have important implications for the design of novel immunotherapeutics for cancer and perhaps autoimmune diseases.
Disclosures
None declared
Mosser D and Briken V: F1000Prime Recommendation of [Manrique SZ et al., J Exp Med 2011, 208(7):1485-99]. In F1000Prime, 07 Jul 2011; DOI: 10.3410/f.11565956.12851055. F1000Prime.com/11565956#eval12851055
20 Jul 2011
New Finding, Novel Drug Target
DOI: 10.3410/f.11565956.13070056
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
This study is the first to identify a new class of macrophage with regulatory properties...Continue reading
This study is the first to identify a new class of macrophage with regulatory properties...Continue reading
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
This study is the first to identify a new class of macrophage with regulatory properties mediated by the forkhead box P3 (FoxP3) transcriptional factor. Similar to their T cell counterparts, these cells possess the capacity to suppress effector T cell activation, but can also induce regulatory T cells. Their regulatory effects are mediated through expression of soluble factors such as prostaglandin E2.
While FoxP3+ macrophages were shown to be capable of suppressing tumour rejection in this paper, their natural role in the regulation of the immune system remains unclear. Perhaps their greatly elevated frequency in the bone marrow compared to other organs may provide a clue as to their function. Nevertheless, these cells may provide an exciting new target for enhancing immunity against cancers.
This study is the first to identify a new class of macrophage with regulatory properties mediated by the forkhead box P3 (FoxP3) transcriptional factor. Similar to their T cell counterparts, these cells possess the capacity to suppress effector T cell activation, but can also induce regulatory T cells. Their regulatory effects are mediated through expression of soluble factors such as prostaglandin E2.
While FoxP3+ macrophages were shown to be capable of suppressing tumour rejection in this paper, their natural role in the regulation of the immune system remains unclear. Perhaps their greatly elevated frequency in the bone marrow compared to other organs may provide a clue as to their function. Nevertheless, these cells may provide an exciting new target for enhancing immunity against cancers.
Disclosures
None declared
Basten A and Silveira P: F1000Prime Recommendation of [Manrique SZ et al., J Exp Med 2011, 208(7):1485-99]. In F1000Prime, 20 Jul 2011; DOI: 10.3410/f.11565956.13070056. F1000Prime.com/11565956#eval13070056
02 Aug 2011
New Finding
DOI: 10.3410/f.11565956.13557055
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
This study is of note because it describes a unique population of macrophages that...Continue reading
This study is of note because it describes a unique population of macrophages that...Continue reading
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
This study is of note because it describes a unique population of macrophages that are Foxp3+ and can suppress T cell proliferation. The gene expression profiles of the Foxp3+ macrophages are distinct form those expressed by Foxp3- macrophages.
An increase in arginase 1 and prostaglandin E2 is observed in the Foxp3+ cells and may explain their suppressive function. Much work remains to be done to determine any role for these 'regulatory' macrophages in controlling immune responses.
This study is of note because it describes a unique population of macrophages that are Foxp3+ and can suppress T cell proliferation. The gene expression profiles of the Foxp3+ macrophages are distinct form those expressed by Foxp3- macrophages.
An increase in arginase 1 and prostaglandin E2 is observed in the Foxp3+ cells and may explain their suppressive function. Much work remains to be done to determine any role for these 'regulatory' macrophages in controlling immune responses.
Disclosures
None declared
Keegan A: F1000Prime Recommendation of [Manrique SZ et al., J Exp Med 2011, 208(7):1485-99]. In F1000Prime, 02 Aug 2011; DOI: 10.3410/f.11565956.13557055. F1000Prime.com/11565956#eval13557055
15 Aug 2011
New Finding, Novel Drug Target
DOI: 10.3410/f.11565956.13694054
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
In this study, Zorro Manrique et al. identify a population of Foxp3-expressing...Continue reading
In this study, Zorro Manrique et al. identify a population of Foxp3-expressing...Continue reading
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
In this study, Zorro Manrique et al. identify a population of Foxp3-expressing macrophages that have immunosuppressive properties and promote tumor growth, thus presenting a possible future therapeutic target for cancer treatment.
While studying regulatory T cells (Tregs), which are defined by their expression of the transcription factor Foxp3, the authors notice that a subpopulation of CD11b+F4/80+ cells in both primary and secondary lymphoid tissues also express Foxp3. They show that these Foxp3-expressing macrophages are just as efficient at suppressing CD4+ T cell proliferation as CD4+ Tregs. Suppression is cell contact-independent and mediated by prostaglandin E2 (PGE2). They also investigate the role of these macrophages in a mouse melanoma model. In addition to Tregs, Foxp3-expressing macrophages are present in significant numbers in these tumors, and co-injection with tumor cells promotes tumor growth. Intriguingly, F4/80-deficient mice fail to support tumor development, but this is rescued by co-injection of Foxp3-expressing macrophages with the tumor cells. This study identifies Foxp3+ macrophages, in addition to Tregs, as a potential target for cancer immunotherapy.
In this study, Zorro Manrique et al. identify a population of Foxp3-expressing macrophages that have immunosuppressive properties and promote tumor growth, thus presenting a possible future therapeutic target for cancer treatment.
While studying regulatory T cells (Tregs), which are defined by their expression of the transcription factor Foxp3, the authors notice that a subpopulation of CD11b+F4/80+ cells in both primary and secondary lymphoid tissues also express Foxp3. They show that these Foxp3-expressing macrophages are just as efficient at suppressing CD4+ T cell proliferation as CD4+ Tregs. Suppression is cell contact-independent and mediated by prostaglandin E2 (PGE2). They also investigate the role of these macrophages in a mouse melanoma model. In addition to Tregs, Foxp3-expressing macrophages are present in significant numbers in these tumors, and co-injection with tumor cells promotes tumor growth. Intriguingly, F4/80-deficient mice fail to support tumor development, but this is rescued by co-injection of Foxp3-expressing macrophages with the tumor cells. This study identifies Foxp3+ macrophages, in addition to Tregs, as a potential target for cancer immunotherapy.
Disclosures
None declared
Underhill D and Goodridge H: F1000Prime Recommendation of [Manrique SZ et al., J Exp Med 2011, 208(7):1485-99]. In F1000Prime, 15 Aug 2011; DOI: 10.3410/f.11565956.13694054. F1000Prime.com/11565956#eval13694054
17 Aug 2011
Devendra Agrawal
F1000 Rheumatology & Clinical Immunology
Creighton University School of Medicine,
Omaha, NE, USA.
F1000 Rheumatology & Clinical Immunology
Creighton University School of Medicine,
Omaha, NE, USA.
Vineet Agrawal
F1000 Rheumatology & Clinical Immunology
University of Pittsburgh Medical Center,
Pittsburgh, PA, USA.
F1000 Rheumatology & Clinical Immunology
University of Pittsburgh Medical Center,
Pittsburgh, PA, USA.
DOI: 10.3410/f.11565956.13992054
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
The transcription factor forkhead box P3 (Foxp3) has been identified within a subset...Continue reading
The transcription factor forkhead box P3 (Foxp3) has been identified within a subset...Continue reading
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
The transcription factor forkhead box P3 (Foxp3) has been identified within a subset of T cells, T regulatory (Treg) cells, that have long been studied for their suppressive role in both normal and disease conditions. For the first time, Zorro Manrique and colleagues demonstrate that a subset of macrophage cells also expresses the transcription factor Foxp3 and displays similar immunosuppressive properties in vitro and in vivo.
We agree with the critical review by Volker Briken and David Mosser. The finding of Foxp3+ cells with cell surface marker expression and functional characteristics consistent with monocytes/macrophages challenges the existing dogma that Treg cells are the primary regulators of a local immune phenotype and polarization. However, we would like to add a few points to the excellent critique by Volker Briken and David Mosser. Zorro Manrique and colleagues clearly demonstrated the expression of Foxp3 in macrophages and showed that these cells can functionally inhibit T cell proliferation through a prostaglandin E2 (PGE2)-dependent mechanism. However, it is interesting that the Foxp3 expression in macrophages can be induced to similar levels by both pro- and anti-inflammatory factors (LPS, CpG, TGF-beta, VEGF). Thus, the mechanisms underlying induction of Foxp3 in macrophages may be an avenue for future investigation.
Additionally, the authors showed that Foxp3- macrophages can be converted into Foxp3+ macrophages. It would also be interesting to see if Foxp3+ macrophages can de-differentiate to a Foxp3- state. If indeed Foxp3+ macrophages play an important role in disease progression, approaches that aim to revert macrophages back to a Foxp3- state might represent a feasible therapeutic intervention.
While it remains to be seen whether the findings of Zorro Manrique and colleagues can be replicated in human monocytes/macrophages, the present study nevertheless contributes to our growing understanding of the active role that the innate immune response plays in both normal and disease conditions. Although the focus of the present manuscript was upon the role Foxp3+ macrophages in tumor progression, it is likely that such cells may also contribute to other diseases processes in which Treg cells have been identified as key regulatory cells. Such processes include asthma, atherosclerosis and transplant rejection. The findings of Zorro Manrique and colleagues serve as the fundamental basis to further investigate the role of Foxp3+ macrophages in these other disease conditions.
The transcription factor forkhead box P3 (Foxp3) has been identified within a subset of T cells, T regulatory (Treg) cells, that have long been studied for their suppressive role in both normal and disease conditions. For the first time, Zorro Manrique and colleagues demonstrate that a subset of macrophage cells also expresses the transcription factor Foxp3 and displays similar immunosuppressive properties in vitro and in vivo.
We agree with the critical review by Volker Briken and David Mosser. The finding of Foxp3+ cells with cell surface marker expression and functional characteristics consistent with monocytes/macrophages challenges the existing dogma that Treg cells are the primary regulators of a local immune phenotype and polarization. However, we would like to add a few points to the excellent critique by Volker Briken and David Mosser. Zorro Manrique and colleagues clearly demonstrated the expression of Foxp3 in macrophages and showed that these cells can functionally inhibit T cell proliferation through a prostaglandin E2 (PGE2)-dependent mechanism. However, it is interesting that the Foxp3 expression in macrophages can be induced to similar levels by both pro- and anti-inflammatory factors (LPS, CpG, TGF-beta, VEGF). Thus, the mechanisms underlying induction of Foxp3 in macrophages may be an avenue for future investigation.
Additionally, the authors showed that Foxp3- macrophages can be converted into Foxp3+ macrophages. It would also be interesting to see if Foxp3+ macrophages can de-differentiate to a Foxp3- state. If indeed Foxp3+ macrophages play an important role in disease progression, approaches that aim to revert macrophages back to a Foxp3- state might represent a feasible therapeutic intervention.
While it remains to be seen whether the findings of Zorro Manrique and colleagues can be replicated in human monocytes/macrophages, the present study nevertheless contributes to our growing understanding of the active role that the innate immune response plays in both normal and disease conditions. Although the focus of the present manuscript was upon the role Foxp3+ macrophages in tumor progression, it is likely that such cells may also contribute to other diseases processes in which Treg cells have been identified as key regulatory cells. Such processes include asthma, atherosclerosis and transplant rejection. The findings of Zorro Manrique and colleagues serve as the fundamental basis to further investigate the role of Foxp3+ macrophages in these other disease conditions.
Disclosures
None declared
Agrawal D and Agrawal V: F1000Prime Recommendation of [Manrique SZ et al., J Exp Med 2011, 208(7):1485-99]. In F1000Prime, 17 Aug 2011; DOI: 10.3410/f.11565956.13992054. F1000Prime.com/11565956#eval13992054
23 Aug 2011
New Finding
DOI: 10.3410/f.11565956.14097055
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
This work newly identifies macrophages expressing Foxp3 and shows that, similarly...Continue reading
This work newly identifies macrophages expressing Foxp3 and shows that, similarly...Continue reading
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
This work newly identifies macrophages expressing Foxp3 and shows that, similarly to T cells expressing Foxp3 that suppress T cell responses, Foxp3+ macrophages are immunosuppressive.
This work newly identifies macrophages expressing Foxp3 and shows that, similarly to T cells expressing Foxp3 that suppress T cell responses, Foxp3+ macrophages are immunosuppressive.
Disclosures
None declared
Bhandoola A: F1000Prime Recommendation of [Manrique SZ et al., J Exp Med 2011, 208(7):1485-99]. In F1000Prime, 23 Aug 2011; DOI: 10.3410/f.11565956.14097055. F1000Prime.com/11565956#eval14097055
14 Sep 2011
New Finding, Novel Drug Target
DOI: 10.3410/f.11565956.14588058
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
This beautiful study by Manrique et al. identifies a new subpopulation of macrophages...Continue reading
This beautiful study by Manrique et al. identifies a new subpopulation of macrophages...Continue reading
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
This beautiful study by Manrique et al. identifies a new subpopulation of macrophages that are Foxp3-positive and that can suppress T cell proliferation, independently of cell-cell contact, induce T regulatory (Treg) cells and promote tumor growth.
Previous evaluations have highlighted the increased expression of immunosuppressive markers in Foxp3-positive macrophages that may explain their suppressive function, providing a novel avenue for therapeutic intervention in cancer immunotherapy.
In this evaluation we would like to emphasize the robust upregulation of complement proteins in these Foxp3-positive macrophages. While both activators (properdin, also known as cfp, and factor B, also known as cfb) and negative regulators (CD55) of the alternative pathway are increased somewhat in Foxp-3 positive macrophages, expression of early components of the classical complement cascade including C1q, C1r, C2 and C4 are substantially increased, suggesting that classical complement components can be locally produced by these cells, providing the components needed for activation of the classical complement pathway. These results are in accordance with a previous study by Markiewski et al. {1} showing that the classical pathway is the main contributor to complement activation in the TC-1 syngeneic model of cervical cancer. Interestingly, Foxp3-positive macrophages showed also increased expression of C5aR1 (CD88) (the receptor of the activation fragment C5a), which was associated with tumor growth since pharmacological blockade of C5aR impaired tumor growth through decreased myeloid-derived suppressor cell (MDSC) infiltration in tumors {1}. It would be very interesting then to see if blockade of C5aR would also affect the number and/or immunosuppressive functions of Foxp3-positive macrophages and whether complement inhibition can override the tumor-dependent immunosuppression induced by Foxp3-positive macrophages.
This beautiful study by Manrique et al. identifies a new subpopulation of macrophages that are Foxp3-positive and that can suppress T cell proliferation, independently of cell-cell contact, induce T regulatory (Treg) cells and promote tumor growth.
Previous evaluations have highlighted the increased expression of immunosuppressive markers in Foxp3-positive macrophages that may explain their suppressive function, providing a novel avenue for therapeutic intervention in cancer immunotherapy.
In this evaluation we would like to emphasize the robust upregulation of complement proteins in these Foxp3-positive macrophages. While both activators (properdin, also known as cfp, and factor B, also known as cfb) and negative regulators (CD55) of the alternative pathway are increased somewhat in Foxp-3 positive macrophages, expression of early components of the classical complement cascade including C1q, C1r, C2 and C4 are substantially increased, suggesting that classical complement components can be locally produced by these cells, providing the components needed for activation of the classical complement pathway. These results are in accordance with a previous study by Markiewski et al. {1} showing that the classical pathway is the main contributor to complement activation in the TC-1 syngeneic model of cervical cancer. Interestingly, Foxp3-positive macrophages showed also increased expression of C5aR1 (CD88) (the receptor of the activation fragment C5a), which was associated with tumor growth since pharmacological blockade of C5aR impaired tumor growth through decreased myeloid-derived suppressor cell (MDSC) infiltration in tumors {1}. It would be very interesting then to see if blockade of C5aR would also affect the number and/or immunosuppressive functions of Foxp3-positive macrophages and whether complement inhibition can override the tumor-dependent immunosuppression induced by Foxp3-positive macrophages.
References
1.
Modulation of the antitumor immune response by complement.
Nat Immunol 2008 Nov; 11(9):1225-35
PMID: 18820683
Disclosures
None declared
Tenner A and Benoit M: F1000Prime Recommendation of [Manrique SZ et al., J Exp Med 2011, 208(7):1485-99]. In F1000Prime, 14 Sep 2011; DOI: 10.3410/f.11565956.14588058. F1000Prime.com/11565956#eval14588058
20 Sep 2011
DOI: 10.3410/f.11565956.14604055
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
This manuscript shows that macrophage-like cells possess a regulatory function...Continue reading
This manuscript shows that macrophage-like cells possess a regulatory function...Continue reading
** NOTE FROM EDITORIAL: Since being evaluated, this article has been retracted (for more details see http://jem.rupress.org/content/early/2011/11/10/jem.2010073020812r.full?sid=03f4544c-3482-4ca3-b215-93e88f9dc7d5) **
This manuscript shows that macrophage-like cells possess a regulatory function previously thought to be the exclusive domain of T cells and suggests that forkhead box P3 (FOXP3) may play a role in poor control of some tumors.
It has been known for many years that macrophages play a crucial regulatory role as they are able to promote inflammation via production of T cell-differentiating factors such as interleukin (IL)-12 and IL-18 and direct mediators such as tumor necrosis factor (TNF)-alpha, or develop into anti-inflammatory cells (so-called 'alternately activated macrophages') under the influence of IL-4. Their biological importance has been indicated by their association with nematode infection, allergic pulmonary inflammation or tumors (where they are called 'tumor associated macrophages' or 'tumor infiltrating macrophages'). Their presence is associated with low inflammatory responses and poorer ability to control pathogens or tumors {1,2}. On the positive side, it's also been suggested that macrophage-like cells play a role in inducing tolerance {3} – including the ability to maintain pregnancy {4}.
It has now been shown in this manuscript that macrophages can also express the transcription factor FOXP3, which is the characteristic marker for regulatory T cells (Treg cells). It was found that FOXP3+ macrophages could inhibit CD4+ T cell proliferation in vitro, and knockdown of FOXP3 expression in these macrophages removed their ability to inhibit T cell proliferation. Finally, the authors showed elevated numbers of FOXP3+ macrophages in the early stages of tumor development in a mouse model, and they showed that transferring FOXP3+ macrophages together with tumor cells resulted in tumor growth in mice that are normally not permissive for those tumors. These studies definitively extend the range of regulatory activities attributable to macrophage-like cells and suggest they play a biologically significant role. It is likely that in other diseases where FOXP3 has been suggested to be a marker for poorer outcomes – such as tuberculosis – the role of FOXP3+ macrophages will need to be examined.
This manuscript shows that macrophage-like cells possess a regulatory function previously thought to be the exclusive domain of T cells and suggests that forkhead box P3 (FOXP3) may play a role in poor control of some tumors.
It has been known for many years that macrophages play a crucial regulatory role as they are able to promote inflammation via production of T cell-differentiating factors such as interleukin (IL)-12 and IL-18 and direct mediators such as tumor necrosis factor (TNF)-alpha, or develop into anti-inflammatory cells (so-called 'alternately activated macrophages') under the influence of IL-4. Their biological importance has been indicated by their association with nematode infection, allergic pulmonary inflammation or tumors (where they are called 'tumor associated macrophages' or 'tumor infiltrating macrophages'). Their presence is associated with low inflammatory responses and poorer ability to control pathogens or tumors {1,2}. On the positive side, it's also been suggested that macrophage-like cells play a role in inducing tolerance {3} – including the ability to maintain pregnancy {4}.
It has now been shown in this manuscript that macrophages can also express the transcription factor FOXP3, which is the characteristic marker for regulatory T cells (Treg cells). It was found that FOXP3+ macrophages could inhibit CD4+ T cell proliferation in vitro, and knockdown of FOXP3 expression in these macrophages removed their ability to inhibit T cell proliferation. Finally, the authors showed elevated numbers of FOXP3+ macrophages in the early stages of tumor development in a mouse model, and they showed that transferring FOXP3+ macrophages together with tumor cells resulted in tumor growth in mice that are normally not permissive for those tumors. These studies definitively extend the range of regulatory activities attributable to macrophage-like cells and suggest they play a biologically significant role. It is likely that in other diseases where FOXP3 has been suggested to be a marker for poorer outcomes – such as tuberculosis – the role of FOXP3+ macrophages will need to be examined.
References
1.
IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype.
BMC Immunol 2002 Jul 4; (3):7
PMID: 12098359
2.
Tumor-associated macrophages in breast cancer as potential biomarkers for new treatments and diagnostics.
Expert Rev Mol Diagn 2011 Jan; 1(11):91-100
PMID: 21171924
3.
Oral macrophage-like cells play a key role in tolerance induction following sublingual immunotherapy of asthmatic mice.
Mucosal Immunol 2011 Nov; 6(4):638-47
PMID: 21775981
4.
Pregnancy-specific glycoprotein gene expression in recurrent aborters: a potential correlation to interleukin-10 expression.
Am J Reprod Immunol 1999 Mar; 3(41):174-82
PMID: 10326620
Disclosures
None declared
Doherty M: F1000Prime Recommendation of [Manrique SZ et al., J Exp Med 2011, 208(7):1485-99]. In F1000Prime, 20 Sep 2011; DOI: 10.3410/f.11565956.14604055. F1000Prime.com/11565956#eval14604055
F1000Prime Recommendations, Dissents and Comments for [Manrique SZ et al., J Exp Med 2011, 208(7):1485-99]. In F1000Prime, 23 May 2013; F1000Prime.com/11565956
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Comment by:
Achsah Keegan,
University of Maryland School of Medicine
Evaluator | 29 Nov 2011, 3:19 PM
Evaluator | 29 Nov 2011, 3:19 PM
This article was retracted because Dr. Lustgarten unfortunately passed away and is not available to respond to queries about the precise methods used and results presented in this paper. Unfortunately, the retraction did not specify any particular data set that was in question.
The concept that macrophages can be immunosuppressive is not outlandish. They can produce arginase and IL-10 previously shown to inhibit T-cell function. However, their ability to express Foxp3 and suppress T-cells via PG was a novel finding. The ability of macrophages to express Foxp3 could be easily confirmed or refuted using Foxp3-GFP reporter mice.
The concept that macrophages can be immunosuppressive is not outlandish. They can produce arginase and IL-10 previously shown to inhibit T-cell function. However, their ability to express Foxp3 and suppress T-cells via PG was a novel finding. The ability of macrophages to express Foxp3 could be easily confirmed or refuted using Foxp3-GFP reporter mice.
Disclosures:
None declared.
Comment by:
Mark Doherty,
GlaxoSmithKline
Evaluator | 20 Nov 2011, 8:29 PM
Evaluator | 20 Nov 2011, 8:29 PM
We'll just have to wait and see how this pans out: although the article was retracted - because the author is no longer around to answer technical requests - there is no suggestion so far that anything was amiss about the work. That said, until another group can confirm the results, that throws this discovery into limbo.
Disclosures:
None declared.
Regulatory T cells (T reg cells) are characterized by the expression of the forkhead lineage-specific transcription factor Foxp3, and their main function is to suppress T cells. While evaluating T reg cells, we identified a population of Foxp3-positive cells that were CD11b(+)F4/80(+)CD68(+), indicating macrophage origin. These cells were observed in spleen, lymph nodes, bone marrow, thymus, liver, and other tissues of naive animals. To characterize this subpopulation of macrophages, we devised a strategy to purify CD11b(+)F4/80(+)Foxp3(+) macrophages using Foxp3-GFP mice. Analysis of CD11b(+)F4/80(+)Foxp3(+) macrophage function indicated that these cells inhibited the proliferation of T cells, whereas Foxp3(-) macrophages did not. Suppression of T cell proliferation was mediated through soluble factors. Foxp3(-) macrophages acquired Foxp3 expression after activation, which conferred inhibitory properties that were indistinguishable from natural Foxp3(+) macrophages. The cytokine and transcriptional profiles of Foxp3(+) macrophages were distinct from those of Foxp3(-) macrophages, indicating that these cells have different biological functions. Functional in vivo analyses indicated that CD11b(+)F4/80(+)Foxp3(+) macrophages are important in tumor promotion and the induction of T reg cell conversion. For the first time, these studies demonstrate the existence of a distinct subpopulation of naturally occurring macrophage regulatory cells in which expression of Foxp3 correlates with suppressive function.
DOI: 10.1084/jem.20100730
PMID: 21670203
