This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Central nervous system (CNS) injury and neurodegenerative conditions are associated with elevated reactive oxygen species (ROS), which are in turn associated with neuronal death. T cells reactive against CNS-specific antigens were shown to induce neuroprotection on injured neural tissue. While the precise mechanism of immune neuroprotection is not fully understood, it is, at least partially, mediated via microglial cells. Suppressor sub-population of T cells (naturally occurring regulatory T cells, Treg) attenuate or block immune neuroprotection by suppressing antigen-specific neuroprotective T cells. Regulation of an antigen specific T cell immune response is an obscure process and is one of the most controversial topics in immunology. Naturally occurring Treg cells suppress immunological T cell reactions in vivo and in vitro. However, the mechanism of inhibition of antigen-specific T cell proliferation by regulatory T cells is a subject of debate. While a significant amount of work provides evidence of soluble factor-mediated suppression, other experiments argue in favor of cell-to-cell contact requirement between Treg and antigen presenting cells to achieve inhibition of effector T cells. Changes occurring in antigen presenting cells, among which are microglia, following interaction with Treg that lead to suppression of effector T cells, are not yet fully understood. Recently, it was proposed that T lymphocytes are incapable of cystine uptake, due to the lack of a cystine transporter, but can import cysteine. Antigen presenting cells release cysteine in the extracellular space thus providing a reducing microenvironment that facilitates the immune response. Moreover, bidirectional interaction of antigen-presenting cells with T cells induces further production and release of cysteine and secreted thioredoxin (TRX) and further boosts the immune response. We propose that Treg cells suppress the release of cysteine and TRX from antigen presenting cells and thus suppress an immune response. Moreover, we posit that release of cysteine and TRX by microglial cells following interaction with T cells serves, at least in part, as a mechanism underlying T cell mediated neuroprotection. Inhibition of this response by Treg cells attenuates neuroprotection by both suppression of a neuroprotective immune response and elimination of an ROS scavenger source.
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