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...