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Invariant natural killer T cells (iNKT cells) constitute a specialized subset of lymphocytes that bridges innate and adaptive immunity through a combination of traits characteristic of both conventional T cells and innate immune cells. iNKT cells are characterized by their invariant T cell receptors and discerning recognition of lipid antigens, which are presented by the non-classical MHC molecule, CD1d. Within the hepatic milieu, iNKT cells hold heightened prominence, contributing significantly to the orchestration of organ homeostasis. Their unique positioning to interact with diverse cellular entities, ranging from epithelial constituents like hepatocytes and cholangiocytes to immunocytes including Kupffer cells, B cells, T cells, and dendritic cells, imparts them with potent immunoregulatory abilities. Emergering knowledge of liver iNKT cells subsets enable to explore their therapeutic potential in autoimmne liver diseases. This comprehensive review navigates the landscape of iNKT cell investigations in immune-mediated cholangiopathies, with a particular focus on primary biliary cholangitis and primary sclerosing cholangitis, across murine models and human subjects to unravel the intricate involvements of iNKT cells in liver autoimmunity. Additionally, we also highlight the prospectives of iNKT cells as therapeutic targets in cholangiopathies. Modulation of the equilibrium between regulatory and proinflammatory iNKT subsets can be defining determinant in the dynamics of hepatic autoimmunity. This discernment not only enriches our foundational comprehension but also lays the groundwork for pioneering strategies to navigate the multifaceted landscape of liver autoimmunity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Channakeshava Sokke Umeshappa reports financial support and article publishing charges were provided by Dalhousie University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The intestinal microbiota is critical for the development of gut-associated lymphoid tissues, including Peyer's patches and mesenteric lymph nodes, and is instrumental in educating the local as well as systemic immune system. In addition, it also impacts the development and function of peripheral organs, such as liver, lung, and the brain, in health and disease. However, whether and how the intestinal microbiota has an impact on T cell ontogeny in the hymus remains largely unclear. Recently, the impact of molecules and metabolites derived from the intestinal microbiota on T cell ontogeny in the thymus has been investigated in more detail. In this review, we will discuss the recent findings in the emerging field of the gut-thymus axis and we will highlight the current questions and challenges in the field., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The gut microbiota contributes to the development of normal immunity but, when dysregulated, can promote autoimmunity through various non-antigen-specific effects on pathogenic and regulatory lymphocytes. Here, we show that an integrase expressed by several species of the gut microbial genus Bacteroides encodes a low-avidity mimotope of the pancreatic β cell autoantigen islet-specific glucose-6-phosphatase-catalytic-subunit-related protein (IGRP 206-214 ). Studies in germ-free mice monocolonized with integrase-competent, integrase-deficient, and integrase-transgenic Bacteroides demonstrate that the microbial epitope promotes the recruitment of diabetogenic CD8+ T cells to the gut. There, these effectors suppress colitis by targeting microbial antigen-loaded, antigen-presenting cells in an integrin β7-, perforin-, and major histocompatibility complex class I-dependent manner. Like their murine counterparts, human peripheral blood T cells also recognize Bacteroides integrase. These data suggest that gut microbial antigen-specific cytotoxic T cells may have therapeutic value in inflammatory bowel disease and unearth molecular mimicry as a novel mechanism by which the gut microbiota can regulate normal immune homeostasis. PAPERCLIP., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Adenoviral (AdV) vectors represent most commonly utilized viral vaccines in clinical studies. While the role of CD8(+) cytotoxic T lymphocyte (CTL) responses in mediating AdV-induced protection is well understood, the involvement of CD4(+) T cell-provided signals in the development of functional CD8(+) CTL responses remain unclear. To explore CD4(+) T helper signals required for AdVova-stimulated CTL responses, we established an adoptive transfer system by transferring CD4(+) T cells derived from various knock out and transgenic mice into wild-type and/or CD4-deficient animals, followed by immunizing with recombinant ovalbumin (OVA)-expressing AdVova vector. Without CD4(+) T help, both primary and memory CTL responses were greatly reduced in this model, and were associated with increased PD-1 expression. The provision of OVA-specific CD4(+) T help in CD4(+) T cell-deficient mice restored AdVova-induced primary CTL responses, and supported survival and recall responses of AdVova-stimulated memory CTLs. These effects were specifically mediated by CD4(+) T cell-produced IL-2 and CD154 signals. Adoptive transfer of "helped" or "unhelped" effector and memory CTLs into naïve CD4(+) T cell-deficient or -sufficient mice also revealed an additional role for polyclonal CD4(+) T cell environment in the survival of AdVova-stimulated CTLs, partially explaining the extension of CTL contraction phase. Finally, during recall responses, CD4(+) T cell environment, particularly involving memory CD4(+) T cells, greatly enhanced expansion of memory CTLs. Collectively, our data strongly suggest a critical role for CD4(+) T help in multiple phases of AdV-stimulated CTL responses, and could partially explain certain failures in AdV-based immunization trials targeting malignant tumors and chronic diseases that are often associated with compromised CD4(+) T cell population and function.