Glycolysis Promotes Autoantibody Production See article p. 377

Galectin-8 Stalls Innate Immunity to PseudomonasSee article p. 398

Arginase 1 in Macrophages Drives Fungal Disease See article p. 408

Thymic Regeneration in Prostate Cancer Treatment See article p. 496

Gliomas Inhibit T Cells through Calcineurin See article p. 504

The thymus and number of recent thymic emigrants (RTEs) shrink in response to sex hormones that become more prevalent as an individual ages. In this Top Read, Polesso et al. (p. 496) explored the impact of androgen deprivation therapy (ADT) on T cell antitumor responses. Since the standard treatment for prostate cancer blocks androgen, the authors investigated whether this therapy may lead to increased thymic activity and antitumor immunity. Using a mouse model, the authors showed that ADT promotes thymic regeneration and RTEs by inducing thymic epithelial cell proliferation. Furthermore, in vivo fate mapping experiments revealed that RTEs migrate to prostate tumors and produce proinflammatory cytokines, including TNFα and IFN-γ, at comparable levels to non-RTEs. This study demonstrates that ADT leads to increased thymic output, which could be leveraged to enhance cancer immunotherapies.

Pseudomonas aeruginosa infection in the eye can cause a hyperactive, dysregulated immune response that leads to severe and irreparable corneal damage, known as P. aeruginosa keratitis (PA keratitis). In this Top Read, Ramadan et al. (p. 398) reported a proinflammatory role for Galectin-8 (Gal-8) in increasing susceptibility to PA keratitis. Initial experiments using Gal-8−/− mice demonstrated that Gal-8 does not affect bacterial growth, suggesting its involvement in the immune response to infection. In corneal neutrophils of Gal-8−/− mice, innate immune and reactive oxygen species (ROS) production pathway genes were upregulated. Proteins regulated by TLR4, such as pro-IL-1β, NLRP3, and procaspase-1, as well as ROS levels were increased in the mutant neutrophils. In addition, Gal-8−/− neutrophils better reduced P. aeruginosa colonies compared with their wild-type counterparts, an effect that was reversed upon application of exogenous Gal-8. In wild-type mice, pharmacological inhibition of Gal-8 prior to infection prevented PA keratitis. Mechanistically, Gal-8 treatment of LPS-stimulated bone marrow–derived macrophages reduced TNFα and IL-6 secretion and prevented the formation of the MD-2/TLR4 complex by binding directly to CD14, but not to LPS or TLR4. Altogether, the data demonstrate that Gal-8 drives PA keratitis by binding directly to CD14 and ultimately inhibiting the formation of MD-2/TLR4 complexes, thus impeding the innate immune response to P. aeruginosa.

In this Top Read, Afsari et al. (p. 504) showed that d-2-hydroxyglutarate (D2HG) can suppress tumor immune surveillance by inhibiting IL-2 expression in T cells. Increased levels of D2HG are found in the tumor microenvironment of most gliomas. Low intracellular levels of D2HG and its chiral pair, L2HG, were present in PBLs and Jurkat T lymphocytes, suggesting they are a natural lymphocyte metabolite. Exogenous addition of either D2HG or L2HG to PBLs and Jurkat T lymphocytes resulted in increased intracellular levels in a stereoselective, concentration-dependent process. However, only D2HG was found to bind calcineurin and inhibit its phosphatase activity, preventing NFAT dephosphorylation. Levels of D2HG that are physiologically relevant to the tumor microenvironment were sufficient to inhibit IL-2 expression in PBL and Jurkat T lymphocytes. Together, these data demonstrate that tumor-produced D2HG is a calcineurin phosphatase inhibitor that can abolish IL-2 expression in T cells.

In this Top Read, Hansakon et al. (p. 408) performed in vivo and in vitro infections with a highly virulent strain of Cryptococcus neoformans to unravel mechanisms that underlie the pathogenic role of macrophages in fungal disease. Transcriptomic analysis of alveolar macrophages at several timepoints postinfection demonstrated a change in macrophage phenotype from inflammatory M1-like to M2-like. During peak fungal infection, Arg1 was the most upregulated gene. Importantly, Arg1 expression positively correlated with fungal burden in the brain but not in the lung. Inhibition of Arg1 in bone marrow–derived macrophages induced a M1 macrophage phenotype and reduced their phagocytic index, intracellular cryptococcal load, and cryptococcal intracellular proliferation. In an in vitro blood brain barrier model, cocultures of M2 or unpolarized, but not M1, macrophages induced extensive endothelial cell infection. Altogether, the data suggest that C. neoformans manipulates macrophage polarization via upregulation of Arg1 to drive fungal meningoencephalitis.

Previous work has shown that inhibiting glycolysis limits systemic lupus erythematosus (SLE) in mouse models. In this Top Read, Abboud et al. (p. 377) investigated whether autoreactive B and T cells require glycolysis to induce SLE. First, the authors showed that activation of monoclonal B cells with a cognate SLE Ag in vitro induced glycolysis at elevated levels compared with nonspecific stimulation with a TLR agonist. However, glycolytic inhibition using a glucose analog restricted autoreactive B cell activation and autoantibody production. This phenomenon occurred both in the presence and absence of T cell help. In contrast to Ag-specific B cells, inhibiting glycolysis in chromatin-specific T cells had no impact on their differentiation to T follicular helper cells. These results suggest that Ag-specific B cells, but not T cells, require glycolysis during SLE, which may guide future SLE immunotherapy.