Highlights d Environmental stiffness promotes DC inflammatory function d Tension primes DC metabolism, even without pattern recognition receptor input d TAZ bridges mechanosensory signals to DC metabolism and function d Tension directs phenotypes of human monocyte-derived DCs

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.

No abstract

CD8 T cells are the major effector cells that protect against malaria liver-stage infection, forming clusters around -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 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. 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 -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 parasites.