Abstract
Vδ2neg γδ T cells, of which Vδ1+ γδ T cells are by far the largest subset, are important effectors against CMV infection. Malignant gliomas often contain CMV genetic material and proteins, and evidence exists that CMV infection may be associated with initiation and/or progression of glioblastoma multiforme (GBM). We sought to determine if Vδ1+ γδ T cells were cytotoxic to GBM and the extent to which their cytotoxicity was CMV dependent. We examined the cytotoxic effect of ex vivo expanded/activated Vδ1+ γδ T cells from healthy CMV seropositive and CMV seronegative donors on unmanipulated and CMV-infected established GBM cell lines and cell lines developed from short- term culture of primary tumors. Expanded/activated Vδ1+ T cells killed CMV-negative U251, U87, and U373 GBM cell lines and two primary tumor explants regardless of the serologic status of the donor. Experimental CMV infection did not increase Vδ1+ T cell - mediated cytotoxicity and in some cases the cell lines were more resistant to lysis when infected with CMV. Flow cytometry analysis of CMV-infected cell lines revealed down-regulation of the NKG2D ligands ULBP-2, and ULBP-3 as well as MICA/B in CMV-infected cells. These studies show that ex vivo expanded/activated Vδ1+ γδ T cells readily recognize and kill established GBM cell lines and primary tumor-derived GBM cells regardless of whether CMV infection is present, however, CMV may enhance the resistance GBM cell lines to innate recognition possibly contributing to the poor immunogenicity of GBM.
Highlights
High-grade gliomas such as glioblastoma multiforme (GBM) can initiate and progress to an unsalvageable point without generating a significant immune response, consistent with Medawar’s description of the brain as a site of relative immune protection [1]
Peripheral blood cd T cells obtained from patients prior to treatment and GBM-infiltrating cd T cells obtained from resected tumor show minimal response to ex vivo stimulation
We cultured peripheral blood mononuclear cells (MNC) from five GBM patients in an effort to determine whether the Vd1+ T cells could respond to ex vivo stimuli and whether sufficient numbers of cells could be obtained for cloning and assay for anti-CMV activity
Summary
High-grade gliomas such as glioblastoma multiforme (GBM) can initiate and progress to an unsalvageable point without generating a significant immune response, consistent with Medawar’s description of the brain as a site of relative immune protection [1]. Human cytomegalovirus (HCMV) infection has been detected in a large percentage of human high-grade gliomas, and recent studies suggest a relationship between HCMV infection and initiation and/or progression of GBM [2–6]. Tcells bearing the c and d receptor (cd T cells) are important effectors against malignancy-associated viral infections such as EBV [12] and HSV [13]. Increases principally in circulating Vd1+, and to a lesser extent Vd3+ and Vd5+ T cell subsets [14], have been strongly and positively correlated with a response to and subsequent resolution of HCMV viremia [15]. CMV-reactive Vd1+ cd T cells are crossreactive against several malignant cell lines [15–18]
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