Malignant pleural effusion (MPE) is a significant clinical problem caused by pleural metastasis of adenocarcinomas or by malignant pleural mesothelioma (1). Treatment is palliative and consists of pleural fluid removal or pleural space obliteration (2). This approach is consistent with the traditional view of MPE pathogenesis, which is that pleural fluid accumulation in patients with cancer is caused by tumor spread to the pleural surfaces with tumorigenic obstruction of lymphatic evacuation tracts (3). In recent years, immunocompetent mouse models of adenocarcinoma-induced MPE were developed and reported in American Thoracic Society journals (4, 5). These models revealed that an inflammatory signaling network between tumor cells and host vascular and immune systems contributes to MPE development. Therapeutic targeting of this crosstalk using clinically relevant methods has yielded meaningful benefits for experimental animals (6, 7). Until recently, the focus of translational MPE research was restricted to deciphering the crosstalk between tumor cells and myeloid immune cells, such as macrophages and granulocytes (5-8). In this issue of the Journal (pp. 697-706), Lin and coworkers report the contrasting functions of two helper T-lymphocyte (Th) subsets, Th1 and Th17, in two different mouse models of lung and colon adenocarcinoma-caused MPE (9). After identifying CD4+ Th1 and Th17 cells in MPE, the investigators used transgenic mice lacking IFN-g and IL-17A to show dependence of Th1 and Th17 cells on IFN-g and IL-17A, respectively. They further attempted to characterize the transcriptional programs required for IFN-g-dependent Th1 and IL-17A-dependent Th17 differentiation, and found them to include, respectively, transcription factors signal transducer and activator of transcription 3 (STAT3)/T-bet and STAT1/RAR-related orphan receptor-gt (Figure 1). Most importantly, the authors convincingly show that these two lymphocyte subsets impact MPE development. IFN-g-deficient mice, devoid of Th1 and rich in Th17 cells, were protected from MPE, whereas IL-17A-deficient mice, rich in Th1 and devoid of Th17 cells, had enhanced pleural fluid accumulation and tumor spread. The study by Lin and coworkers expands on previous observations of this group regarding lymphocytes in human and mouse MPE (10-12) by showing for the first time that T-cell subsets are involved in sculpting the pleural microenvironment that regulates intrapleural tumor dissemination and fluid accumulation. In addition to myeloid subsets like macrophages (7, 8), neutrophils (13), and eosinophils (5), previously shown to impact MPE pathobiology, these studies clarify a role for T cells in pleural tumor progression. Despite these important findings, the precise way in which T cells affect pleural fluid homeostasis is not clear. Do they influence tumor cells and the pleural vasculature directly by secreting tumorigenic and vasoactive mediators, or, alternatively, do T cells fine-tune other (myeloid) effector cells? In addition, Th1 cells and IFN-g have traditionally been reported to mediate antitumor immunity (14), which contrasts with the results of Lin and colleagues and raises the possibility that the pleural microenvironment is special (3). These issues will likely be the topics of future studies. The study by Lin and colleagues highlights the importance of immunocompetent models of cancer in the struggle to better understand the involvement of the immune system in pleural cancer biology. Studies that use human cancer cells in immunocompromised mice pioneered MPE research and have their own merits (4, 6), but the studies by Lin and colleagues would not have been …