Crotty and colleagues define the gene targets of BCL6 in primary human follicular T helper cells, revealing its primary role as a gene repressor. BCL6 bound to some loci directly and to others by interacting with AP1 and being recruited to canonical AP1-binding sites.
Differentiation of T helper (TH) effector subsets is critical for host protection. E protein transcription factors and Id proteins are important arbiters of T cell development, but their role in differentiation of TH1 and TFH cells is not well understood. TH1 cells showed robust Id2 expression compared to TFH cells, and RNAi depletion of Id2 increased TFH cell frequencies. Further, TH1 cell differentiation was blocked by Id2 deficiency, leading to E protein-dependent accumulation of effector cells with mixed characteristics during viral infection and severely impaired generation of TH1 cells following Toxoplasma gondii infection. The TFH-defining transcriptional repressor Bcl6 bound the Id2 locus, providing a mechanism for the bimodal Id2 expression and reciprocal development of TH1 and TFH cell fates.
Chronic infections represent a continuous battle between the host's immune system and pathogen replication. Many protozoan parasites have evolved a cyst lifecycle stage that provides it with increased protection from environmental degradation as well as endogenous host mechanisms of attack. In the case of Toxoplasma gondii, these cysts are predominantly found in the immune protected brain making clearance of the parasite more difficult and resulting in a lifelong infection. Currently, little is known about the nature of the immune response stimulated by the presence of these cysts or how they are able to propagate. Here we establish a novel chitinase-dependent mechanism of cyst control in the infected brain. Despite a dominant Th1 immune response during Toxoplasma infection there exists a population of alternatively activated macrophages (AAMØ) in the infected CNS. These cells are capable of cyst lysis via the production of AMCase as revealed by live imaging, and this chitinase is necessary for protective immunity within the CNS. These data demonstrate chitinase activity in the brain in response to a protozoan pathogen and provide a novel mechanism to facilitate cyst clearance during chronic infections.
The chemokine receptor CCR7 is a well-established homing receptor for dendritic cells and T cells. Interactions with its ligands, CCL19 and CCL21, facilitate priming of immune responses in lymphoid tissue, yet CCR7-independent immune responses can be generated in the presence of sufficient antigen. In these studies, we investigated the role of CCR7 signaling in the generation of protective immune responses to the intracellular protozoan parasite Toxoplasma gondii. The results demonstrated a significant increase in the expression of CCL19, CCL21, and CCR7 in peripheral and central nervous system (CNS) tissues over the course of infection. Unexpectedly, despite the presence of abundant antigen, CCR7 was an absolute requirement for protective immunity to T. gondii, as CCR7 ؊/؊ mice succumbed to the parasite early in the acute phase of infection. Although serum levels of interleukin 12 (IL-12), IL-6, tumor necrosis factor alpha (TNF-␣), and IL-10 remained unchanged, there was a significant decrease in CCL2/monocyte chemoattractant protein 1 (MCP-1) and inflammatory monocyte recruitment to the site of infection. In addition, CCR7؊/؊ mice failed to produce sufficient gamma interferon (IFN-␥), a critical Th1-associated effector cytokine required to control parasite replication. As a result, there was increased parasite dissemination and a significant increase in parasite burden in the lungs, livers, and brains of infected mice. Adoptive-transfer experiments revealed that expression of CCR7 on the T-cell compartment alone is sufficient to enable T-cell priming, increase IFN-␥ production, and allow the survival of CCR7؊/؊ mice. These data demonstrate an absolute requirement for T-cell expression of CCR7 for the generation of protective immune responses to Toxoplasma infection.The chemokine receptor CCR7 and its ligands, CCL19 and CCL21, are known to be critical for a number of essential immunological processes throughout the development of an immune response. These include the generation of thymocytes (6, 26), central and peripheral tolerance, T-cell homeostasis (36), regulatory T-cell (T reg ) function (23,29,40), and the activation and homing of CCR7-expressing dendritic cells to lymph nodes (12,28,32). This central role is in part due to the constitutive expression of CCL19 and CCL21 in primary and secondary lymphoid organs and their roles in guiding the migration of developing, naïve, and central memory T cells. CCL21 is expressed on the high endothelial vessels (HEVs) of the lymph node and by fibroblastic reticular cells (FRC) and follicular dendritic cells (FDC) forming the conduits that are the structural core of the lymph node (2, 33). These structures enable the migration and interaction of CCR7 ϩ cells, namely, naïve or memory T cells and dendritic cells (DCs). Following CCR7-mediated entry into the lymphatics, DCs present antigen to naïve T cells within the lymph node paracortex. T cells enter the lymph node via HEVs and show a "haptokinetic" mode of migration on the FRC surface in response to immobilized CCL2...
Chronic infection with the intracellular protozoan parasite Toxoplasma gondii leads to tissue remodelling in the brain and a continuous requirement for peripheral leucocyte migration within the CNS (central nervous system). In the present study, we investigate the role of MMPs (matrix metalloproteinases) and their inhibitors in T-cell migration into the infected brain. Increased expression of two key molecules, MMP-8 and MMP-10, along with their inhibitor, TIMP-1 (tissue inhibitor of metalloproteinases-1), was observed in the CNS following infection. Analysis of infiltrating lymphocytes demonstrated MMP-8 and -10 production by CD4+ and CD8+ T-cells. In addition, infiltrating T-cells and CNS resident astrocytes increased their expression of TIMP-1 following infection. TIMP-1-deficient mice had a decrease in perivascular accumulation of lymphocyte populations, yet an increase in the proportion of CD4+ T-cells that had trafficked into the CNS. This was accompanied by a reduction in parasite burden in the brain. Taken together, these findings demonstrate a role for MMPs and TIMP-1 in the trafficking of lymphocytes into the CNS during chronic infection in the brain.
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