Specific recruitment of regulatory T cells into the CSF in lymphomatous and carcinomatous meningitis

Whereas regulatory T (T-reg) cells play an important role in the prevention of autoimmunity, increasing evidence suggests that their down-regulatory properties negatively affect immune responses directed against tumors. T-reg cells 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 T-reg-cell accumulation within the subarachnoid space as a result of interfering with tumor immunity may be relevant for survival of neoplastic cells. We collected cerebrospinal fluid (CSF) from 101 patients diagnosed with lymphomatouls/ carcinomatous NM and various inflammatory diseases (IDs) and noninflammatory neurologic disorders (NIDs). CSF T-reg-cell counts were determined by flow cytometry, T-reg cell-specific chemokines by enzyme-linked immunsorbent assay (ELISA), and T-reg-cell trafficking by chemotaxis assay. Both frequencies of T-reg-cell and T-reg cell-specific chemotactic activities were significantly elevated in CSF samples of patients with NM. Local T-reg-cell accumulation occurred without concomitant rise of conventional T (T-conv) cells, coincided with elevated concentrations of T-reg cell-attracting chemokines CCL17 and CCL22 and correlated with numbers of atypical CSF cells. We conclude that T-reg cells are specifically recruited into the CSF of patients with NM, suggesting that the presence of T-reg cells within the subarachnoid space generates a microenvironment that may favor survival and growth of malignant cells.