Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance

Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):4215-20. doi: 10.1073/pnas.1320924111. Epub 2014 Mar 3.


Tolerance to apoptotic cells is essential to prevent inflammatory pathology. Though innate responses are critical for immune suppression, our understanding of early innate immunity driven by apoptosis is lacking. Herein we report apoptotic cells induce expression of the chemokine CCL22 in splenic metallophillic macrophages, which is critical for tolerance. Systemic challenge with apoptotic cells induced rapid production of CCL22 in CD169(+) (metallophillic) macrophages, resulting in accumulation and activation of FoxP3(+) Tregs and CD11c(+) dendritic cells, an effect that could be inhibited by antagonizing CCL22-driven chemotaxis. This mechanism was essential for suppression after apoptotic cell challenge, because neutralizing CCL22 or its receptor, reducing Treg numbers, or blocking effector mechanisms abrogated splenic TGF-β and IL-10 induction; this promoted a shift to proinflammatory cytokines associated with a failure to suppress T cells. Similarly, CCR4 inhibition blocked long-term, apoptotic cell-induced tolerance to allografts. Finally, CCR4 inhibition resulted in a systemic breakdown of tolerance to self after apoptotic cell injection with rapid increases in anti-dsDNA IgG and immune complex deposition. Thus, the data demonstrate CCL22-dependent chemotaxis is a key early innate response required for apoptotic cell-induced suppression, implicating a previously unknown mechanism of macrophage-dependent coordination of early events leading to stable tolerance.

Keywords: autoimmunity; migration; regulation; spleen; transplantation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / immunology*
  • Cell Movement / physiology
  • Chemokine CCL22 / immunology*
  • Chemokine CCL22 / metabolism
  • Cytokines / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Immunohistochemistry
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, CCR4 / genetics
  • Sialic Acid Binding Ig-like Lectin 1 / immunology*
  • Sialic Acid Binding Ig-like Lectin 1 / metabolism
  • Transplantation Tolerance / genetics
  • Transplantation Tolerance / immunology*


  • Ccr4 protein, mouse
  • Chemokine CCL22
  • Cytokines
  • Receptors, CCR4
  • Sialic Acid Binding Ig-like Lectin 1
  • Siglec1 protein, mouse