CSF-1–Dependent Red Pulp Macrophages Regulate CD4 T Cell Responses

The balance between immune activation and suppression must be regulated to maintain immune homeostasis. Tissue macrophages (MΦs) constitute the major cellular subsets of APCs within the body; however, how and what types of resident MΦs are involved in the regulation of immune homeostasis in the peripheral lymphoid tissues are poorly understood. Splenic red pulp MΦ (RPMs) remove self-Ags, such as blood-borne particulates and aged erythrocytes, from the blood. Although many scattered T cells exist in the red pulp of the spleen, little attention has been given to how RPMs prevent harmful T cell immune responses against self-Ags. In this study, we found that murine splenic F4/80hiMac-1low MΦs residing in the red pulp showed different expression patterns of surface markers compared with F4/80+Mac-1hi monocytes/MΦs. Studies with purified cell populations demonstrated that F4/80hiMac-1low MΦs regulated CD4+ T cell responses by producing soluble suppressive factors, including TGF-β and IL-10. Moreover, F4/80hiMac-1low MΦs induced the differentiation of naive CD4+ T cells into functional Foxp3+ regulatory T cells. Additionally, we found that the differentiation of F4/80hiMac-1low MΦs was critically regulated by CSF-1, and in vitro-generated bone marrow-derived MΦs induced by CSF-1 suppressed CD4+ T cell responses and induced the generation of Foxp3+ regulatory T cells in vivo. These results suggested that splenic CSF-1–dependent F4/80hiMac-1low MΦs are a subpopulation of RPMs and regulate peripheral immune homeostasis.

[1]  W. Wiktor-Jedrzejczak,et al.  Colony-stimulating factor 1-dependent resident macrophages play a regulatory role in fighting Escherichia coli fecal peritonitis , 1996, Infection and immunity.

[2]  J. van Krieken,et al.  Normal histology of the human spleen. , 1988, The American journal of surgical pathology.

[3]  A. Minami,et al.  α9 Integrin and Its Ligands Constitute Critical Joint Microenvironments for Development of Autoimmune Arthritis1 , 2009, The Journal of Immunology.

[4]  A. Rudensky,et al.  Regulatory T cell lineage specification by the forkhead transcription factor foxp3. , 2005, Immunity.

[5]  Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3 , 2003, The Journal of experimental medicine.

[6]  K. Murphy,et al.  Role for SpiC in the development of red pulp macrophages and splenic iron homeostasis , 2008 .

[7]  F. Geissmann,et al.  Blood monocytes: development, heterogeneity, and relationship with dendritic cells. , 2009, Annual review of immunology.

[8]  B. Pulendran,et al.  Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17–producing T cell responses , 2007, Nature Immunology.

[9]  S. Gordon,et al.  Monocyte and macrophage heterogeneity , 2005, Nature Reviews Immunology.

[10]  J. Hamilton Colony-stimulating factors in inflammation and autoimmunity , 2008, Nature Reviews Immunology.

[11]  T. Ottenhoff,et al.  Human Anti-Inflammatory Macrophages Induce Foxp3+GITR+CD25+ Regulatory T Cells, Which Suppress via Membrane-Bound TGFβ-11 , 2008, The Journal of Immunology.

[12]  E. Stanley,et al.  Incomplete restoration of colony-stimulating factor 1 (CSF-1) function in CSF-1-deficient Csf1op/Csf1op mice by transgenic expression of cell surface CSF-1. , 2004, Blood.

[13]  W. Wiktor-Jedrzejczak,et al.  Distinct in vivo functions of two macrophage subpopulations as evidenced by studies using macrophage‐deficient op/op mouse , 1992, European journal of immunology.

[14]  D. Hume,et al.  An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation. , 2010, Blood.

[15]  Angela Hughson,et al.  Early Kinetic Window of Target T Cell Susceptibility to CD25+ Regulatory T Cell Activity1 , 2005, The Journal of Immunology.

[16]  S. Akira,et al.  The Nuclear IκB Protein IκBNS Selectively Inhibits Lipopolysaccharide-Induced IL-6 Production in Macrophages of the Colonic Lamina Propria 1 , 2005, The Journal of Immunology.

[17]  S. Akira,et al.  The nuclear IkappaB protein IkappaBNS selectively inhibits lipopolysaccharide-induced IL-6 production in macrophages of the colonic lamina propria. , 2005, Journal of immunology.

[18]  S. Gordon,et al.  Pattern recognition receptors and differentiation antigens define murine myeloid cell heterogeneity ex vivo , 2003, European journal of immunology.

[19]  A. Halstensen,et al.  Phagocytosis: measurement by flow cytometry. , 2000, Journal of immunological methods.

[20]  G. Geginat,et al.  Dynamic Antigen Presentation Patterns of Listeria monocytogenes-Derived CD8 T Cell Epitopes In Vivo1 , 2001, The Journal of Immunology.

[21]  R. Mebius,et al.  Structure and function of the spleen , 2005, Nature Reviews Immunology.

[22]  G. Geginat,et al.  Cross-Presentation of Listeria monocytogenes-Derived CD4 T Cell Epitopes1 , 2002, The Journal of Immunology.

[23]  H. Weiner,et al.  Myelin Oligodendrocyte Glycoprotein–specific T Cell Receptor Transgenic Mice Develop Spontaneous Autoimmune Optic Neuritis , 2003, The Journal of experimental medicine.

[24]  G. Geginat,et al.  Efficient In Vivo Presentation of Listeria monocytogenes- Derived CD4 and CD8 T Cell Epitopes in the Absence of IFN-γ1 , 2002, The Journal of Immunology.

[25]  Y. Wan,et al.  Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[26]  T. Nomura,et al.  Regulatory T Cells and Immune Tolerance , 2008, Cell.

[27]  B. Pulendran,et al.  Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance. , 2006, The Journal of clinical investigation.

[28]  R. Steinman,et al.  Antibody to Langerin/CD207 localizes large numbers of CD8α+ dendritic cells to the marginal zone of mouse spleen , 2009, Proceedings of the National Academy of Sciences.

[29]  L. Shultz,et al.  Macrophage colony-stimulating factor is indispensable for repopulation and differentiation of Kupffer cells but not for splenic red pulp macrophages in osteopetrotic (op/op) mice after macrophage depletion , 2008, Cell and Tissue Research.

[30]  L. de Leval,et al.  Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice. , 2009, The Journal of clinical investigation.

[31]  C. Glass,et al.  A Subpopulation of Macrophages Infiltrates Hypertrophic Adipose Tissue and Is Activated by Free Fatty Acids via Toll-like Receptors 2 and 4 and JNK-dependent Pathways* , 2007, Journal of Biological Chemistry.

[32]  M. Cesta Normal Structure, Function, and Histology of the Spleen , 2006, Toxicologic pathology.

[33]  S. Gordon,et al.  Dectin‐2 is predominantly myeloid restricted and exhibits unique activation‐dependent expression on maturing inflammatory monocytes elicited in vivo , 2005, European journal of immunology.

[34]  S Gordon,et al.  Macrophage receptors and immune recognition. , 2005, Annual review of immunology.

[35]  J. Pollard,et al.  Role of colony stimulating factor-1 in the establishment and regulation of tissue macrophages during postnatal development of the mouse. , 1994, Development.

[36]  S. Gaines,et al.  The Mouse , 2011 .

[37]  S. Gordon The macrophage: Past, present and future , 2007, European journal of immunology.

[38]  J. Hermans,et al.  The splenic red pulp; a histomorphometrical study in splenectomy specimens embedded in methylmethacrylate , 1985, Histopathology.

[39]  D. Sheppard,et al.  The Integrin α9β1 Mediates Adhesion to Activated Endothelial Cells and Transendothelial Neutrophil Migration through Interaction with Vascular Cell Adhesion Molecule-1 , 1999, The Journal of cell biology.

[40]  S. Nishikawa,et al.  Effects of macrophage colony‐stimulating factor (M‐CSF) on the development, differentiation, and maturation of marginal metallophilic macrophages and marginal zone macrophages in the spleen of osteopetrosis (op) mutant mice lacking functional M‐CSF activity , 1994, Journal of leukocyte biology.