Submitted August 6, 2007
Accepted October 24, 2007
Specific recruitment of regulatory T-cells into the CSF in lymphomatous and carcinomatous meningitis
Juergen Haas, Laila Schopp, Brigitte Storch-Hagenlocher, Benedikt Fritzsching, Christian Jacobi, Linda Milkova, Brigitte Fritz, Alexander Schwarz, Elisabeth Suri-Payer, Manfred Hensel, and Brigitte Wildemann*
Division of Molecular Neuroimmunology, Dept of Neurology, University of Heidelberg, Heidelberg, Germany
Dept of Neonatology, Children's Hospital, University of Heidelberg, Heidelberg, Germany
Division of Immunogenetics/Tumorimmunology Program, German Cancer Research Center, Heidelberg, Germany
Dept of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
* Corresponding author; email: brigitte_wildemann{at}med.uni-heidelberg.de.
Whereas regulatory T-cells (Treg) play an important role in the prevention of autoimmunity increasing evidence suggests that their downregulatory properties negatively affect immune responses directed against tumors. Treg selectively express chemokine receptors CCR4 and CCR8 and specific migration occurs following the release of various chemokines. Neoplastic meningitis (NM) resulting from leptomeningeal spread of systemic non Hodgkin lymphoma (NHL) or carcinoma has a poor prognosis. We hypothesized that Treg accumulation within the subarachnoid space by interfering with tumor immunity may be relevant for survival of neoplastic cells. We collected CSF from 101 patients diagnosed with lymphomatous/carcinomatous NM and various inflammatory (ID) and non-inflammatory neurologic disorders (NID). CSF Treg-counts were determined by flow cytometry, Treg-specific chemokines by ELISA, and Treg-trafficking by chemotaxis assay. Both frequencies of Treg and Treg-specific chemotactic activities were significantly elevated in CSF samples of NM patients. Local Treg accumulation occurred without concomitant rise of Tconv, coincided with elevated concentrations of Treg-attracting chemokines CCL17 and CCL22 and correlated with numbers of atypical CSF cells. We conclude that Treg are specifically recruited into the CSF of NM patients, suggesting that the presence of Treg within the subarachnoid space generates a microenvironment which may favor survival and growth of malignant cells.
