Alternatively activated macrophages inhibit T-cell proliferation by Stat6-dependent expression of PD-L2.
Alternatively activated macrophages (AAM) accumulate in tissues during Th2-associated immune responses like helminth infections and allergic disorders. These cells differentiate in response to interleukin 4 (IL-4)/IL-13-mediated activation of Stat6 and possess potent inhibitory activity against T cells. The molecular mechanism that leads to T-cell suppression remains unclear and could involve soluble factors or inhibitory ligands. Microarray analysis revealed that the inhibitory ligand, programmed death ligand 2 (PD-L2) was strongly induced by IL-4 in macrophages from wild-type but not Stat6-deficient mice. PD-L2 expression correlated with other established markers for AAM-like Relm-α/Fizz1, arginase1, or Ym1 and thereby serves as useful surface marker to identify and isolate AAM from tissues. Antibodies against PD-L2 blocked the inhibitory activity of AAM and retroviral expression of PD-L2 in macrophages from Stat6(-/-) mice was sufficient to inhibit T-cell proliferation, which demonstrates that PD-L2 mediates potent and nonredundant inhibition of T cells independently of other Stat6-regulated genes. Infection of conditional IL-4/IL-13-deficient mice with the helminth Nippostrongylus brasiliensis further showed that PD-L2 expression was dependent on IL-4/IL-13 from Th2 cells. In vivo blockade of PD-L2 during N brasiliensis infection caused an enhanced Th2 response in the lung, indicating that AAM inhibit Th2 cells by expression of PD-L2.
Huber
Silke
S
Institute for Immunology, Ludwig-Maximilians-University, Munich, Germany.
Hoffmann
Reinhard
R
Muskens
Femke
F
Voehringer
David
D
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D060890:B7-H1 Antigen; D049109:Cell Proliferation; D002478:Cells, Cultured; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015847:Interleukin-4 / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000469:parasitology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009559:Nippostrongylus / Q000276:immunology*; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology*; D018418:Th2 Cells / Q000276:immunology
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4