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.

Nippostrongylus brasiliensis, STAT6 protein, T lymphocyte, Th2 cell, alternatively activated macrophage, animal cell, animal experiment, animal model, animal tissue, arginase 1, article, cell activity, controlled study, enzyme deficiency, helminthiasis, in vivo study, macrophage, microarray analysis, mouse, nonhuman, priority journal, programmed death 1 ligand 2, protein expression
dx.doi.org/10.1182/blood-2010-02-271981, hdl.handle.net/1765/21637
Blood
Erasmus MC: University Medical Center Rotterdam

Huber, S, Hoffmann, R, Muskens, F, & Voehringer, D. (2010). Alternatively activated macrophages inhibit T-cell proliferation by Stat6-dependent expression of PD-L2. Blood, 116(17), 3311–3320. doi:10.1182/blood-2010-02-271981