In contrast, CD8 Tunc are not affected in CD25?/?, IL-7?/?, IL-6?/? and IFN?/? mice. or T cell-mediated autoimmune diseases. CD8 Tunc are dependent upon IL-15/IL-2R signaling and PLZF for their development and/or survival. They are FoxP3-negative N10 and their regulatory activity is associated with a functionally distinct Qa-1b-dependent population co-expressing MC-Val-Cit-PAB-Retapamulin CD11c and CD244. A polyclonal TCR repertoire, an activated/memory phenotype and the presence of CD8 Tunc in NKT- and in MAIT-deficient, as well as in germ-free mice indicates that these cells recognize diverse self-protein antigens. Our studies reveal a distinct population of unconventional CD8+ T cells within the natural immune repertoire capable of controlling autoimmunity and MC-Val-Cit-PAB-Retapamulin also providing MC-Val-Cit-PAB-Retapamulin a new target for therapeutic intervention. Introduction Liver is a unique organ in that it has a central role in the metabolism and in the maintenance of immune tolerance against a constant exposure to diet and microbial antigens (1). However, at the same time, hepatic immune system needs to provide immunity against chronic infections and cancer metastasis. Thus, immune response in the liver has to be appropriately controlled to avoid excessive tissue damage without compromising the tissue integrity and metabolic functions (2). Liver contains specialized resident immune cells, including tolerogenic antigen-presenting cells (3) as well as adaptive and innate lymphoid cell populations. Particularly, liver is enriched in several innate lymphoid cells that respond rapidly to conserved ligands, including NK cells and unconventional T cells, like NKT cells, mucosal-associated invariant T (MAIT) cells and T cells (4). Unconventional T cells, distinct from conventional class I or class II MHC-restricted T cells, are generally restricted by non-classical MHC class Ib (e.g., Qa-1b/HLA-E, H2-M3) and MHC class-I like (e.g., CD1, MR1) molecules and recognize a different class of non-protein antigens, such as self and microbial lipids and metabolites (4). While significantly more is known about the role of NKT or MAIT cells MC-Val-Cit-PAB-Retapamulin in mounting effector immune responses, little is known about the identity or function MC-Val-Cit-PAB-Retapamulin of other hepatic innate-like T cells involved in controlling immunity. Knowledge of rapidly-acting innate regulatory mechanism(s) is important in understanding how excessive inflammatory responses are controlled to maintain tissue integrity. T cells are controlled by both intrinsic (e.g., PD1, anergy and exhaustion) and extrinsic cell-based (Treg) mechanisms that prevent their over-stimulation. While an important role of FoxP3+CD4+ Treg in homeostasis is abundantly clear (5), the biology of CD8+ T cells with regulatory activity is still incompletely understood despite demonstration of their involvement in immune regulation (6-11). A regulatory role for CD8+ T cells has also been suggested in various conditions in humans, e.g. in transplant survival (12), inflammatory bowel disease (13) and multiple sclerosis (14, 15). Regulatory CD8+ T cells have been identified using cell surface expression of several markers, including CD8, CD122, Ly49 and CD11c (9, 16-19). Since, these molecules are also expressed by activated conventional CD8+ T cells, one of the major issues curtailing a detailed characterization of regulatory CD8+ T cells has been to distinguish them from non-regulatory CD8+ T cells. In this study, for the first time, we have identified a novel, innate-like CD8+TCR+ polyclonal T cell population enriched in the liver of na?ve mice and also present in healthy humans, referred to as CD8 Tunc, which is distinguishable from conventional CD8+ T cells by the expression of the promyelocytic leukemia zinc finger (PLZF) transcription factor. CD8 Tunc control T cell-mediated autoimmunity using a perforin-dependent mechanism and are comprised of a functionally distinct population that co-express CD11c and CD244. It is noteworthy that CD8 Tunc are dependent upon IL-2R signaling and a substantial number of them are Qa-1b-restricted. In summary, our findings reveal a new member of the unconventional T cells with immune regulatory function that can be potentially targeted for intervention in inflammatory diseases. Materials and Methods Ethics statement Animal studies were carried out in strict accordance with the recommendations of the Guide for the Care and.