Although the brain is an immune privileged site, adaptive immunity can provide resistance to various infectious diseases that affect the CMS. This is illustrated by the important role that T cells play in resistance to Toxoplasmic encephalitis (TE) which remains an important disease in patients with primary and acquired immune deficiencies. While many of the factors that lead to acute resistance to Toxoplasma gondii are well characterized, the events that allow control of this pathogen in the brain are poorly understood. Specifically, which cells are involved in local antigen presentation and the effector mechanisms that lead to the control of T. gondii in this unique site are poorly defined. Therefore, in vitro and in vivo studies will be performed to determine which cells can present parasite antigens in the brain and to assess their relative contribution of resident and infiltrating antigen presenting cells to the regulation of protective T cell responses during TE. Additional studies will make use of deep tissue imaging to understand how parasite specific T cells interact with accessory cells (DC and astrocytes) in the brain. The second part of this proposal builds on our observation that mice deficient in the transcription factor NF-KB1 have a major defect in their ability to control parasite replication in the CMS. The mechanism that underlies this phenotype is unclear but preliminary data indicates that astrocytes, but not macrophages, from these mice are compromised in their ability to produce cytokines associated with resistance to TE, have a reduced capacity to stimulate T cell responses and to inhibit parasite replication. Studies are proposed to determine the basis for the increased susceptibility of these mice to TE. Moreover, for over 20 years it has been proposed that astrocytes have a major role in mediating resistance to T. gondii in the CNS. This hypothesis will now be directly tested using mice in which NF-kB signaling pathways are specifically compromised in astrocytes only and the ability of these cells to act as effector cells or as accessory cells that regulate protective T cell responses in the brain will be assessed. Together, these studies will provide new information on the factors associated with the maintenance of local T cell responses required for resistance to TE and the contribution of CNS-resident cells to the control of parasite replication in the brain. This work will broadly advance our understanding of how the immune system functions in the CNS and its role in the control of pathogens in this unique immunological site.
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