12
CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens.
Immunity. 2011 Jan 28; 34(1):85-95
All selected articles haveThis article has been added to your saved articles
You can follow/unfollow articles via MyF1000 or via the article or browse pages.
11 Jan 2011
DOI: 10.3410/f.7450959.7741058
This study comes to the unexpected conclusion that macrophages, not dendritic cells, are the primary antigen presenting cells (APCs) for dead tumor cells.
Many previous studies have shown that migratory dendritic cells deliver antigen to the lymph node where it can be directly presented, or cross-presented...Continue reading
Many previous studies have shown that migratory dendritic cells deliver antigen to the lymph node where it can be directly presented, or cross-presented...Continue reading
This study comes to the unexpected conclusion that macrophages, not dendritic cells, are the primary antigen presenting cells (APCs) for dead tumor cells.
Many previous studies have shown that migratory dendritic cells deliver antigen to the lymph node where it can be directly presented, or cross-presented by other dendritic cells, to CD8+ T cells. Thus, most immunologists would have assumed that antigens derived from dead tumor cells would also be delivered by dendritic cells to the draining lymph nodes for activation of CD8+ T cells. It was thus surprising to find that dead tumor cells directly made their way to the draining lymph node sinuses, within hours, where they were phagocytosed by a non-migratory CD169+ macrophage population. To further verify their role, CD169+ macrophages were specifically depleted in vivo, and anti-tumor activity of CD8+ T cells was impaired (not 'abolished' as the authors declared). The contribution of CD169+ macrophages was not manifested when the antigen was presented in soluble form with adjuvant, but was observed only when the antigen was associated with dead cells, probably through recognition of phosphatidylserine. The results provide information that can help guide optimal use of whole cell vaccines, or possible chemotherapeutic agents, for inducing anti-tumor immunity.
Many previous studies have shown that migratory dendritic cells deliver antigen to the lymph node where it can be directly presented, or cross-presented by other dendritic cells, to CD8+ T cells. Thus, most immunologists would have assumed that antigens derived from dead tumor cells would also be delivered by dendritic cells to the draining lymph nodes for activation of CD8+ T cells. It was thus surprising to find that dead tumor cells directly made their way to the draining lymph node sinuses, within hours, where they were phagocytosed by a non-migratory CD169+ macrophage population. To further verify their role, CD169+ macrophages were specifically depleted in vivo, and anti-tumor activity of CD8+ T cells was impaired (not 'abolished' as the authors declared). The contribution of CD169+ macrophages was not manifested when the antigen was presented in soluble form with adjuvant, but was observed only when the antigen was associated with dead cells, probably through recognition of phosphatidylserine. The results provide information that can help guide optimal use of whole cell vaccines, or possible chemotherapeutic agents, for inducing anti-tumor immunity.
Disclosures
None declared
Add Comment
Kranz D: F1000Prime Recommendation of [Asano K et al., Immunity 2011, 34(1):85-95]. In F1000Prime, 11 Jan 2011; DOI: 10.3410/f.7450959.7741058. F1000Prime.com/7450959#eval7741058
14 Feb 2011
Christian Engwerda
F1000 Immunology
Queensland Institute of Medical Research,
Herston, QLD, Australia.
F1000 Immunology
Queensland Institute of Medical Research,
Herston, QLD, Australia.
Novel Drug Target, Technical Advance
DOI: 10.3410/f.7450959.8702059
This article reports the important observation that CD169-positive macrophages found in the cortical and paracortical sinuses of lymph nodes cross-present dead cell-associated antigen to generate potent CD8+ T cell-mediated anti-tumour immunity.
The authors injected dead tumour cells subcutaneously in...Continue reading
The authors injected dead tumour cells subcutaneously in...Continue reading
This article reports the important observation that CD169-positive macrophages found in the cortical and paracortical sinuses of lymph nodes cross-present dead cell-associated antigen to generate potent CD8+ T cell-mediated anti-tumour immunity.
The authors injected dead tumour cells subcutaneously in mice to generate tumour antigen-specific CD8+ T cells in the draining lymph node. They found that CD169-expressing macrophages captured the dead tumour cells, and, by specifically depleting this cell population, demonstrated they were responsible for generating anti-tumour CD8+ T cells that controlled tumour growth. The CD169-positive macrophages could be divided into two distinct populations, based on expression of CD11c. Those expressing CD11c were found to be responsible for cross-presenting dead cell-associated tumour antigen. An intriguing issue yet to be addressed is whether these CD169+ CD11c+ macrophages are in any way developmentally related to CD8+ CD11c+ dendritic cells because they reside in close proximity to each other and have very similar functions, including interleukin (IL)-12 production and antigen presentation, albeit cross-presentation of cell-associated antigen by CD169+ CD11c+ macrophages and soluble antigen by CD8+ CD11c+ dendritic cells. The findings of this study have direct implications for vaccine design, and in particular, targeting antigen-presenting cells for the generation of optimum immune responses.
The authors injected dead tumour cells subcutaneously in mice to generate tumour antigen-specific CD8+ T cells in the draining lymph node. They found that CD169-expressing macrophages captured the dead tumour cells, and, by specifically depleting this cell population, demonstrated they were responsible for generating anti-tumour CD8+ T cells that controlled tumour growth. The CD169-positive macrophages could be divided into two distinct populations, based on expression of CD11c. Those expressing CD11c were found to be responsible for cross-presenting dead cell-associated tumour antigen. An intriguing issue yet to be addressed is whether these CD169+ CD11c+ macrophages are in any way developmentally related to CD8+ CD11c+ dendritic cells because they reside in close proximity to each other and have very similar functions, including interleukin (IL)-12 production and antigen presentation, albeit cross-presentation of cell-associated antigen by CD169+ CD11c+ macrophages and soluble antigen by CD8+ CD11c+ dendritic cells. The findings of this study have direct implications for vaccine design, and in particular, targeting antigen-presenting cells for the generation of optimum immune responses.
Disclosures
None declared
Engwerda C: F1000Prime Recommendation of [Asano K et al., Immunity 2011, 34(1):85-95]. In F1000Prime, 14 Feb 2011; DOI: 10.3410/f.7450959.8702059. F1000Prime.com/7450959#eval8702059
08 Mar 2011
Technical Advance
DOI: 10.3410/f.7450959.9361054
The authors' use of tools and techniques to trace the macrophage population that traps and processes antigen from dead cells at a distant site is ingenious. The authors make use of several unique mouse strains, including strains where cluster of differentiation (CD)169+ macrophages can be ablated, and...Continue reading
The authors' use of tools and techniques to trace the macrophage population that traps and processes antigen from dead cells at a distant site is ingenious. The authors make use of several unique mouse strains, including strains where cluster of differentiation (CD)169+ macrophages can be ablated, and the 'Kaede' transgenic mouse that expresses a light-activated fluorescent protein. From a technical standpoint alone, this paper is amazing.
This paper tracks down the myeloid lineage cells that capture and present antigen in an experimental scenario of anti-tumor immunity. The authors demonstrate that CD169+ macrophages located between the lymphatic sinus and lymphoid areas trap antigen from dead cells, and subsequently cross-present antigen to elicit an anti-tumor response. Although the present study focuses on an artificial anti-tumor response (using the ovalbumin [OVA] system), the implications of the study are likely to be far more broad, in that the same processes probably exist in many infectious disease contexts, especially those involving immunity in the lung, where antigen will drain into (predominantly) the mediastinal lymph node.
This paper tracks down the myeloid lineage cells that capture and present antigen in an experimental scenario of anti-tumor immunity. The authors demonstrate that CD169+ macrophages located between the lymphatic sinus and lymphoid areas trap antigen from dead cells, and subsequently cross-present antigen to elicit an anti-tumor response. Although the present study focuses on an artificial anti-tumor response (using the ovalbumin [OVA] system), the implications of the study are likely to be far more broad, in that the same processes probably exist in many infectious disease contexts, especially those involving immunity in the lung, where antigen will drain into (predominantly) the mediastinal lymph node.
Disclosures
None declared
Murray P: F1000Prime Recommendation of [Asano K et al., Immunity 2011, 34(1):85-95]. In F1000Prime, 08 Mar 2011; DOI: 10.3410/f.7450959.9361054. F1000Prime.com/7450959#eval9361054
30 Mar 2011
Peter Van Endert
F1000 Immunology
Institut National de la Santé et de la Recherche Médicale,
Paris, France.
F1000 Immunology
Institut National de la Santé et de la Recherche Médicale,
Paris, France.
New Finding, Novel Drug Target
DOI: 10.3410/f.7450959.9949060
This article comes to the surprising conclusion that CD169+ macrophages in the subcapsular lymph node sinus are the principal antigen presenting cells responsible for cross-priming against dead and dying tumor cells.
Recent research has revealed that these cells have an unexpectedly large number of important...Continue reading
Recent research has revealed that these cells have an unexpectedly large number of important...Continue reading
This article comes to the surprising conclusion that CD169+ macrophages in the subcapsular lymph node sinus are the principal antigen presenting cells responsible for cross-priming against dead and dying tumor cells.
Recent research has revealed that these cells have an unexpectedly large number of important biological functions, such as capturing particulate lymph-borne antigens including virions {1}, priming of virus-specific CD8+ T cells {2} and capturing immune complexes and transferring them to B cell follicles {3}. Now Asano and colleagues show that these cells, which are strategically positioned at the lymph node portal, capture dead tumor cells, cross-present tumor cell-derived antigen to CD8+ T cells, and cross-prime tumor-specific cytotoxic T lymphocytes (CTLs) in vivo. Priming is abolished upon depletion of the CD169+ cells, while migratory dermal and CD8+ CD11c+ dendritic cells appear dispensable for priming. These results are unexpected with respect to the commonly assumed pre-eminence of CD8+ CD11c+ dendritic cells in cross-priming. The authors suggest that the latter may primarily act in tolerogenic cross-priming to blood-borne antigens and in cross-priming to soluble lymph-borne antigens. The precise nature and lineage of the CD169+ macrophages is unclear, and the authors cannot rule out that they correspond to a small subset of CD8+ dendritic cells. However, whatever their precise lineage, this paper is the first to find that a population resident in the lymph node subcapsular sinus is critical for cross-priming to dead tumor cells.
Recent research has revealed that these cells have an unexpectedly large number of important biological functions, such as capturing particulate lymph-borne antigens including virions {1}, priming of virus-specific CD8+ T cells {2} and capturing immune complexes and transferring them to B cell follicles {3}. Now Asano and colleagues show that these cells, which are strategically positioned at the lymph node portal, capture dead tumor cells, cross-present tumor cell-derived antigen to CD8+ T cells, and cross-prime tumor-specific cytotoxic T lymphocytes (CTLs) in vivo. Priming is abolished upon depletion of the CD169+ cells, while migratory dermal and CD8+ CD11c+ dendritic cells appear dispensable for priming. These results are unexpected with respect to the commonly assumed pre-eminence of CD8+ CD11c+ dendritic cells in cross-priming. The authors suggest that the latter may primarily act in tolerogenic cross-priming to blood-borne antigens and in cross-priming to soluble lymph-borne antigens. The precise nature and lineage of the CD169+ macrophages is unclear, and the authors cannot rule out that they correspond to a small subset of CD8+ dendritic cells. However, whatever their precise lineage, this paper is the first to find that a population resident in the lymph node subcapsular sinus is critical for cross-priming to dead tumor cells.
References
1.
Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells.
Nature 2007 Nov 1; 7166(450):110-4
PMID: 17934446
2.
Direct priming of antiviral CD8+ T cells in the peripheral interfollicular region of lymph nodes.
Nat Immunol 2008 Feb; 2(9):155-65
PMID: 18193049
3.
Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation.
Nat Immunol 2009 Jul; 7(10):786-93
PMID: 19503106
Disclosures
None declared
Van Endert P: F1000Prime Recommendation of [Asano K et al., Immunity 2011, 34(1):85-95]. In F1000Prime, 30 Mar 2011; DOI: 10.3410/f.7450959.9949060. F1000Prime.com/7450959#eval9949060
08 Apr 2011
New Finding
DOI: 10.3410/f.7450959.9768066
This study shows a new mode of tumor antigen presentation: entry of tumor cells to lymph nodes and dead cell debris to be presented by resting CD169+ macrophages. This is a different mechanism to the current view that dendritic cells catch dead cell debris in tissues and migrate to lymphoid organs to...Continue reading
This study shows a new mode of tumor antigen presentation: entry of tumor cells to lymph nodes and dead cell debris to be presented by resting CD169+ macrophages. This is a different mechanism to the current view that dendritic cells catch dead cell debris in tissues and migrate to lymphoid organs to present antigens to T cells.
These findings provide an interpretation for an early observation by Ralph Zinkernagel and colleagues {1} that direct inoculation of lymph nodes with tumor cells could induce major histocompatibility complex (MHC) class I-restricted CD8+ T cells without (or with minimal) cross-presentation.
These findings provide an interpretation for an early observation by Ralph Zinkernagel and colleagues {1} that direct inoculation of lymph nodes with tumor cells could induce major histocompatibility complex (MHC) class I-restricted CD8+ T cells without (or with minimal) cross-presentation.
References
Disclosures
None declared
Chen L: F1000Prime Recommendation of [Asano K et al., Immunity 2011, 34(1):85-95]. In F1000Prime, 08 Apr 2011; DOI: 10.3410/f.7450959.9768066. F1000Prime.com/7450959#eval9768066
26 Apr 2011
New Finding
DOI: 10.3410/f.7450959.10590068
The authors surprisingly show that CD169+ macrophages, not dendritic cells (DCs), play a major role in cross-presenting tumor-derived antigens to activate cytotoxic T cells in the draining lymph node.
They show that subcutaneous immunization with irradiated tumor cells protects mice from syngenic tumor....Continue reading
They show that subcutaneous immunization with irradiated tumor cells protects mice from syngenic tumor....Continue reading
The authors surprisingly show that CD169+ macrophages, not dendritic cells (DCs), play a major role in cross-presenting tumor-derived antigens to activate cytotoxic T cells in the draining lymph node.
They show that subcutaneous immunization with irradiated tumor cells protects mice from syngenic tumor. However, tumor antigen-specific CD8+ T cell activation and subsequent antitumor immunity are severely impaired in mice depleted with CD169+ macrophages, but neither migratory DCs {1} nor lymph node-resident conventional CD8alpha+ DCs {2,3}, cells well known for their cross-presentation ability.
These findings should improve our understanding of how to generate and activate tumor-specific T cell immunity in response to tumor-cell death.
They show that subcutaneous immunization with irradiated tumor cells protects mice from syngenic tumor. However, tumor antigen-specific CD8+ T cell activation and subsequent antitumor immunity are severely impaired in mice depleted with CD169+ macrophages, but neither migratory DCs {1} nor lymph node-resident conventional CD8alpha+ DCs {2,3}, cells well known for their cross-presentation ability.
These findings should improve our understanding of how to generate and activate tumor-specific T cell immunity in response to tumor-cell death.
References
1.
Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming.
Immunity 2006 Jul; 1(25):153-62
PMID: 16860764
2.
Migratory and lymphoid-resident dendritic cells cooperate to efficiently prime naive CD4 T cells.
Immunity 2008 Nov 14; 5(29):795-806
PMID: 18951047
3.
Differential roles of migratory and resident DCs in T cell priming after mucosal or skin HSV-1 infection.
J Exp Med 2009 Feb 16; 2(206):359-70
PMID: 19153243
Disclosures
None declared
Ma X: F1000Prime Recommendation of [Asano K et al., Immunity 2011, 34(1):85-95]. In F1000Prime, 26 Apr 2011; DOI: 10.3410/f.7450959.10590068. F1000Prime.com/7450959#eval10590068
23 Jun 2011
DOI: 10.3410/f.7450959.12503054
This study brings new insights into relevant antigen presenting cell (APC) populations that cross-present apoptotic cell-associated antigens injected subcutaneously. Additionally, mechanisms of antigen uptake are addressed. Lastly, it is interesting that physical barriers (not mechanistic ones) and...Continue reading
This study brings new insights into relevant antigen presenting cell (APC) populations that cross-present apoptotic cell-associated antigens injected subcutaneously. Additionally, mechanisms of antigen uptake are addressed. Lastly, it is interesting that physical barriers (not mechanistic ones) and cell localization within the lymph node prevent conventional dendritic cells (DCs) from cross-presenting cell-associated antigens in vivo.
In mice, an intravenous injection of apoptotic cells induces tolerance. However, subcutaneous injection of apoptotic cells can result in an immunogenic response in a manner that is dependent on the cell-death stimulus used {1}. The mechanism by which an immunogenic response is acquired is of great interest for the development of improved tumor treatments. Asano et al. demonstrate that apoptotic cells (apoptosis was induced by exposure of cells to X-rays) injected subcutaneously (mouse footpad) are immunogenic (mice develop anti-tumor immunity). They show that the apoptotic cells that reach the draining lymph node are phagocytosed by CD169+ macrophages within a relatively short timeframe (3hrs post injection). The CD169+ macrophages were localized to the sinus of the draining lymph node; conventional CD8 alpha+ DCs were localized in the T-cell zone and thus did not have access to the apoptotic cells. By ablating CD169+ cells, the authors confirmed that CD169+ macrophages are instrumental for priming CD8+ T cells and generating anti-tumor immunity. The authors show that the phagocytosis of the apoptotic cells is dependent on the recognition of exposed phosphatidylserine (PS). Studies from the Kroemer group have proposed that calreticulin (normally an endoplasmic reticulum [ER]-resident chaperone) on the surface of cells treated with specific chemotherapeutic drugs confers immunogenicity to apoptotic tumor cells by promoting their phagocytic uptake {1}. Previous studies have also shown that cell-surface calreticulin of apoptotic cells can promote their phagocytic uptake {2}. It is, thus, of interest to further examine roles for cell-surface calreticulin of live and dying tumor cells in inducing T-cell priming. Lastly, many in vitro cross-priming studies use either bone-marrow-derived DCs or splenic CD8+ DCs. Asano et al. reported that the conventional DCs were able to cross-present cell-associated antigen in vitro, but probably did not have access to the antigen in vivo. Thus, when structuring in vitro experiments, the studies of Asano et al. bring to light how important it is to consider lymph node architecture.
In mice, an intravenous injection of apoptotic cells induces tolerance. However, subcutaneous injection of apoptotic cells can result in an immunogenic response in a manner that is dependent on the cell-death stimulus used {1}. The mechanism by which an immunogenic response is acquired is of great interest for the development of improved tumor treatments. Asano et al. demonstrate that apoptotic cells (apoptosis was induced by exposure of cells to X-rays) injected subcutaneously (mouse footpad) are immunogenic (mice develop anti-tumor immunity). They show that the apoptotic cells that reach the draining lymph node are phagocytosed by CD169+ macrophages within a relatively short timeframe (3hrs post injection). The CD169+ macrophages were localized to the sinus of the draining lymph node; conventional CD8 alpha+ DCs were localized in the T-cell zone and thus did not have access to the apoptotic cells. By ablating CD169+ cells, the authors confirmed that CD169+ macrophages are instrumental for priming CD8+ T cells and generating anti-tumor immunity. The authors show that the phagocytosis of the apoptotic cells is dependent on the recognition of exposed phosphatidylserine (PS). Studies from the Kroemer group have proposed that calreticulin (normally an endoplasmic reticulum [ER]-resident chaperone) on the surface of cells treated with specific chemotherapeutic drugs confers immunogenicity to apoptotic tumor cells by promoting their phagocytic uptake {1}. Previous studies have also shown that cell-surface calreticulin of apoptotic cells can promote their phagocytic uptake {2}. It is, thus, of interest to further examine roles for cell-surface calreticulin of live and dying tumor cells in inducing T-cell priming. Lastly, many in vitro cross-priming studies use either bone-marrow-derived DCs or splenic CD8+ DCs. Asano et al. reported that the conventional DCs were able to cross-present cell-associated antigen in vitro, but probably did not have access to the antigen in vivo. Thus, when structuring in vitro experiments, the studies of Asano et al. bring to light how important it is to consider lymph node architecture.
References
Disclosures
None declared
Raghavan M and Del Cid N: F1000Prime Recommendation of [Asano K et al., Immunity 2011, 34(1):85-95]. In F1000Prime, 23 Jun 2011; DOI: 10.3410/f.7450959.12503054. F1000Prime.com/7450959#eval12503054
F1000Prime Recommendations, Dissents and Comments for [Asano K et al., Immunity 2011, 34(1):85-95]. In F1000Prime, 20 May 2013; F1000Prime.com/7450959
Only registered/signed-in users can make comments.
Sign in or Subscribe to create your user account and join the discussion.
Sign in or Subscribe to create your user account and join the discussion.
No comments yet.
The generation of tumor-directed cytotoxic T lymphocytes is considered crucial for the induction of antitumor immunity. To activate these CD8(+) T cells, antigen-presenting cells (APCs) must initially acquire tumor cell-associated antigens. The major source of tumor antigens is dead tumor cells, but little is known about how APCs in draining lymph nodes acquire and crosspresent these antigens. Here we show that CD169(+) macrophages phagocytose dead tumor cells transported via lymphatic flow and subsequently crosspresent tumor antigens to CD8(+) T cells. Subcutaneous immunization with irradiated tumor cells protects mice from syngenic tumor. However, tumor antigen-specific CD8(+) T cell activation and subsequent antitumor immunity are severely impaired in mice depleted with CD169(+) macrophages. Neither migratory dendritic cells (DCs) nor lymph node-resident conventional DCs are essential for the crosspresentation of tumor antigens. Thus, we have identified CD169(+) macrophages as lymph node-resident APCs dominating early activation of tumor antigen-specific CD8(+) T cells.
Copyright © 2011 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.immuni.2010.12.011
PMID: 21194983
