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Expression and Function of Glial Cell Line-Derived Neurotrophic Factor Family Ligands and Their Receptors on Human Immune Cells¹

Vivian Vargas-Leal^*, Roxana Bruno^*, Tobias Derfuss^*,, Markus Krumbholz^*,, Reinhard Hohlfeld^*, and Edgar Meinl^2,*,

^* Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Martinsried, Germany; and Institute for Clinical Neuroimmunology, Ludwig-Maximilians-University, Munich, Germany

There is increasing evidence that factors originally identified due to their neurotrophic activity also function within the immune system. This study focused on the related molecules glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) as well as their receptors. GDNF and NTN signaling is mediated by a two-component receptor: a signal-transducing component, RET, which is shared by both ligands, and a ligand-specific binding component, GFR-1 (higher GDNF affinity) or GFR-2 (higher NTN affinity). We report that human T cells, B cells, and monocytes produce NTN but not GDNF, as seen by RT-PCR and immunocytochemistry. RET was expressed by B cells, T cells, and monocytes. Exons 2–5 of RET encoding the cadherin-like domains 1–3 in the extracellular part and exons 16–19 encoding a section of the second tyrosine kinase domain were transcribed in CD4⁺ T cells, CD8⁺ T cells, B cells, and monocytes. Different splice variants encoding the C-terminal intracellular part (exons 19–21) of RET were detected. The ligand-binding receptors GFR-1 and GFR-2 were transcribed in all immune cell subsets. Quantitative PCR showed that GFR-2 is by far the dominant ligand binding chain in T cells, B cells, and monocytes. Addition of GDNF or NTN to activated PBMCs reduced the amount of detectable TNF protein without altering its transcription. Together, this suggests that immune cells communicate with each other via NTN. Production of NTN by immune cells might also contribute to the neuroprotective immunity in the CNS observed in different model systems.

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