IRF4 is a transcription factor from the IRF factor family that plays pivotal roles in the differentiation and function of T and B lymphocytes. Although IRF4 is also expressed in dendritic cells (DCs) and macrophages, its roles in these cells in vivo are not clearly understood. In this study, conditional knockout mice that lack IRF4 in DCs or macrophages were generated and infected with Leishmania major. Mice lacking DC expression of IRF4 showed reduced footpad swelling compared with C57BL/6 mice, whereas those lacking IRF4 in macrophages did not. Mice with IRF4-deficient DCs also showed reduced parasite burden, and their CD4⁺ T cells produced higher levels of IFN-γ in response to L. major Ag. In the draining lymph nodes, the proportion of activated CD4⁺ T cells in these mice was similar to that in the control, but the proportion of IFN-γ–producing cells was increased, suggesting a Th1 bias in the immune response. Moreover, the numbers of migrating Langerhans cells and other migratory DCs in the draining lymph nodes were reduced both before and postinfection in mice with IRF4 defects in DCs, but higher levels of IL-12 were observed in IRF4-deficient DCs. These results imply that IRF4 expression in DCs inhibits their ability to produce IL-12 while promoting their migratory behavior, thus regulating CD4⁺ T cell responses against local infection with L. major.

Hydrogen sulfide (H₂S) is the latest member of the gasotransmitter family and known to play essential roles in cancer pathophysiology. H₂S is produced endogenously and can be administered exogenously. Recent studies showed that H₂S in cancers has both pro- and antitumor roles. Understanding the difference in the expression and localization of tissue-specific H₂S-producing enzymes in healthy and cancer tissues allows us to develop tools for cancer diagnosis and treatment. Urological malignancies are some of the most common cancers in both men and women, and their early detection is vital since advanced cancers are recurrent, metastatic, and often resistant to treatment. This review summarizes the roles of H₂S in cancer and looks at current studies investigating H₂S activity and expression of H₂S-producing enzymes in urinary cancers. We specifically focused on urothelial carcinoma, renal cell carcinoma, and prostate cancer, as they form the majority of newly diagnosed urinary cancers. Recent studies show that besides the physiological activity of H₂S in cancer cells, there are patterns between the development and prognosis of urinary cancers and the expression of H₂S-producing enzymes and indirectly the H₂S levels. Though controversial and not completely understood, studying the expression of H₂S-producing enzymes in cancer tissue may represent an avenue for novel diagnostic and therapeutic strategies for addressing urological malignancies.

Adaptive immune responses are critical for protection against infection with Plasmodium parasites. The metabolic state dramatically changes in T cells during activation and the memory phase. Recent findings suggest that metformin, a medication for treating type-II diabetes, enhances T-cell immune responses by modulating lymphocyte metabolism. In this study, we investigated whether metformin could enhance anti-malaria immunity. Mice were infected with Plasmodium yoelii and administered metformin. Levels of parasitemia were reduced in treated mice compared with those in untreated mice, starting at ~2 weeks post-infection. The number of γδ T cells dramatically increased in the spleens of treated mice compared with that in untreated mice during the later phase of infection, while that of αβ T cells did not. The proportions of Vγ1⁺ and Vγ2⁺ γδ T cells increased, suggesting that activated cells were selectively expanded. However, these γδ T cells expressed inhibitory receptors and had severe defects in cytokine production, suggesting that they were in a state of exhaustion. Metformin was unable to rescue the cells from exhaustion at this stage. Depletion of γδ T cells with antibody treatment did not affect the reduction of parasitemia in metformin-treated mice, suggesting that the effect of metformin on the reduction of parasitemia was independent of γδ T cells.

CD8 ⁺ T cells are the major effector cells that protect against malaria liver-stage infection, forming clusters around Plasmodium -infected hepatocytes and eliminating parasites after a prolonged interaction with these hepatocytes. We aimed to investigate the roles of specific and nonspecific CD8 ⁺ T cells in cluster formation and protective immunity. To this end, we used Plasmodium berghei ANKA expressing ovalbumin as well as CD8 ⁺ T cells from transgenic mice expressing a T cell receptor specific for ovalbumin (OT-I) and CD8 ⁺ T cells specific for an unrelated antigen, respectively. While antigen-specific CD8 ⁺ T cells were essential for cluster formation, both antigen-specific and nonspecific CD8 ⁺ T cells joined the clusters. However, nonspecific CD8 ⁺ T cells did not significantly contribute to protective immunity. In the livers of infected mice, specific CD8 ⁺ T cells expressed high levels of CD25, compatible with a local, activated effector phenotype. In vivo imaging of the liver revealed that specific CD8 ⁺ T cells interact with CD11c ⁺ cells around infected hepatocytes. The depletion of CD11c ⁺ cells virtually eliminated the clusters in the liver, leading to a significant decrease in protection. These experiments reveal an essential role of hepatic CD11c ⁺ dendritic cells and presumably macrophages in the formation of CD8 ⁺ T cell clusters around Plasmodium -infected hepatocytes. Once cluster formation is triggered by parasite-specific CD8 ⁺ T cells, specific and unrelated activated CD8 ⁺ T cells join the clusters in a chemokine- and dendritic cell-dependent manner. Nonspecific CD8 ⁺ T cells seem to play a limited role in protective immunity against Plasmodium parasites.