Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic.

We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-CreER mice (Nf1flox/wt; Cx3cr1-CreER mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells.

T lymphocytes as dynamic regulators of glioma pathobiology.

The brain tumor microenvironment contains numerous distinct types of nonneoplastic cells, which each serve a diverse set of roles relevant to the formation, maintenance, and progression of these central nervous system cancers. While varying in frequencies, monocytes (macrophages, microglia, and myeloid-derived suppressor cells), dendritic cells, natural killer cells, and T lymphocytes represent the most common nonneoplastic cellular constituents in low- and high-grade gliomas (astrocytomas). Although T cells are conventionally thought to target and eliminate neoplastic cells, T cells also exist in other states, characterized by tolerance, ignorance, anergy, and exhaustion. In addition, T cells can function as drivers of brain cancer growth, especially in low-grade gliomas. Since T cells originate in the blood and bone marrow sinuses, their capacity to function as both positive and negative regulators of glioma growth has ignited renewed interest in their deployment as immunotherapeutic agents. In this review, we discuss the roles of T cells in low- and high-grade glioma formation and progression, as well as the potential uses of modified T lymphocytes for brain cancer therapeutics.