Distinct PLZF+CD8αα+ Unconventional T Cells Enriched in Liver Use a Cytotoxic Mechanism to Limit Autoimmunity.

Hepatic immune system is uniquely challenged to mount a controlled effector response to pathogens while maintaining tolerance to diet and microbial Ags. We have identified a novel population of innate-like, unconventional CD8αα+TCRαß+ T cells in naive mice and in human peripheral blood, called CD8αα Tunc, capable of controlling effector T cell responses. They are NK1.1+ (CD161+ in human), express NK-inhibitory receptors, and express the promyelocytic leukemia zinc finger (PLZF) transcription factor that distinguishes them from conventional CD8+ T cells. These cells display a cytotoxic phenotype and use a perforin-dependent mechanism to control Ag-induced or T cell-mediated autoimmune diseases. CD8αα Tunc are dependent upon IL-15/IL-2Rß signaling and PLZF for their development and/or survival. They are Foxp3-negative and their regulatory activity is associated with a functionally distinct Qa-1b-dependent population coexpressing CD11c and CD244. A polyclonal TCR repertoire, an activated/memory phenotype, and the presence of CD8αα Tunc in NKT- and in MAIT-deficient as well as in germ-free mice indicates that these cells recognize diverse self-protein Ags. Our studies reveal a distinct population of unconventional CD8+ T cells within the natural immune repertoire capable of controlling autoimmunity and also providing a new target for therapeutic intervention.

Dendritic cells use endocytic pathway for cross-priming class Ib MHC-restricted CD8alphaalpha+TCRalphabeta+ T cells with regulatory properties.

Understanding the mechanisms leading to effective priming of lymphocytes with regulatory properties is crucial for the manipulation of immune responses. CD8alphaalpha(+)TCRalphabeta(+) T cells are a special subset of innate-like lymphocytes that have been shown to be involved in immune regulation. These cells can recognize self-peptides in the context of a class Ib molecule, Qa-1. How self-Ags are processed in the Qa-1 pathway and presented to CD8alphaalpha(+)TCRalphabeta(+) T cells is not understood. In this study we demonstrate a cross-presentation pathway by which bone marrow-derived dendritic cells (DCs) capture apoptotic CD4(+) T cells and process and present TCR-derived peptides in the context of Qa-1 to prime CD8alphaalpha(+)TCRalphabeta(+) T cells. The priming ability of the DCs is enhanced following TLR signaling using TLR3, TLR4, and TLR9 agonists. DC-mediated cross-presentation is inhibited in the presence of endosomal and proteasomal Ag-processing antagonists. Importantly, DCs loaded with apoptotic T cells prime CD8alphaalpha(+)TCRalphabeta(+) T cells in vivo, which in turn provides protection from CD4(+) T cell-mediated autoimmune disease. These data provide a key insight related to processing and presentation of self-Ags in the Qa-1 pathway for priming of CD8alphaalpha(+)TCRalphabeta(+) T cells and have implications for a DC-based immunotherapeutic approach to inflammatory diseases.

Global expression profiling of peripheral Qa-1-restricted CD8αα+TCRαß+ regulatory T cells reveals innate-like features: implications for immune-regulatory repertoire.

Among peripheral regulatory T cells, CD8(+) T cells also play an important role in the maintenance of immune homeostasis. A subset of CD8(+) Treg that express αß T cell receptor (TCR) and CD8αα homodimers can recognize TCR-derived peptides in the context of the class Ib MHC molecule Qa-1. To gain a better understanding of the nature and phenotype of CD8αα(+)TCRαß+ Treg, a global gene expression profiling using microarray, real-time quantitative polymerase chain reaction, and flow-cytometric analysis was performed using functional Treg clones and lines. The study findings show that CD8(+) Treg shared gene profile expressed by innate-like lymphocytes, including murine intraepithelial lymphocytes and thymic CD8αα(+)TCRαß+ T-cell populations. In addition, this subset displays differential expression of several key regulatory molecules, including CD200. CD8αα(+) Treg expressed higher levels of a number of natural killer cell-related receptors and molecules belonging to the TNF superfamily. Collectively, peripheral class Ib-reactive CD8αα(+)TCRαß+ T cells represent a unique regulatory population different from class Ia major histocompatibility complex-restricted conventional T cells. These studies have important implications for the regulatory mechanisms mediated by the CD8(+) Treg population in general.