Re-programming mouse liver-resident invariant natural killer T cells for suppressing hepatic and diabetogenic autoimmunity

Abstract

Invariant NKT (iNKT) cells comprise a heterogeneous group of non-circulating, tissue-resident T lymphocytes that recognize glycolipids, including alpha-galactosylceramide (αGalCer), in the context of CD1d, but whether peripheral iNKT cell subsets are terminally differentiated remains unclear. Here we show that mouse and human liver-resident αGalCer/CD1d-binding iNKTs largely correspond to a novel Zbtb16+Tbx21+Gata3+MaflowRorc– subset that exhibits profound transcriptional, phenotypic and functional plasticity. Repetitive in vivo encounters of these liver iNKT (LiNKT) cells with intravenously delivered αGalCer/CD1d-coated nanoparticles (NP) trigger their differentiation into immunoregulatory, IL-10+IL-21-producing Zbtb16highMafhighTbx21+Gata3+Rorc– cells, termed LiNKTR1, expressing a T regulatory type 1 (TR1)-like transcriptional signature. This response is LiNKT-specific, since neither lung nor splenic tissue-resident iNKT cells from αGalCer/CD1d-NP-treated mice produce IL-10 or IL-21. Additionally, these LiNKTR1 cells suppress autoantigen presentation, and recognize CD1d expressed on conventional B cells to induce IL-10+IL-35-producing regulatory B (Breg) cells, leading to the suppression of liver and pancreas autoimmunity. Our results thus suggest that LiNKT cells are plastic for further functional diversification, with such plasticity potentially targetable for suppressing tissue-specific inflammatory phenomena.

Advancing Tolerogenic Immunotherapy: A Multi-Epitope Vaccine Design Targeting the CYP2D6 Autoantigen in Autoimmune Hepatitis Through Immuno-Informatics

“…This transformation fosters a local immunosuppressive environment and facilitates the conversion of local dendritic cells (DCs) into tolerogenic DCs, thereby impeding the progression of autoimmune pathologies. Importantly, these regulatory T cells do not compromise local or systemic immunity against infection and cancer, indicating their safety for use in autoimmune patients [12, 14, 15]. The underlying reprogramming mechanisms are largely orchestrated by the regulatory cytokine IL-10.…”

“…Unlike traditional immunogenic vaccines that are designed to prevent infections, these tolerogenic vaccines aim to dampen immune responses Specifically, interactions between regulatory T cells and APCs stimulate local IL-10 production, which suppresses antigen presentation, T cell activation, and recruitment [15]. Moreover, IL-10 production via TR1 interactions promotes B-cell differentiation into tolerogenic APCs [12,14], effectively halting the generation of autoreactive T and B cells and thereby controlling autoimmunity.…”

“…Similarly, observed interactions between IL-10 and IL-10RA indicate IL-10's ability to provide tolerogenic signals to DCs. MD simulations further validated the stability of interactions within the docked complexes, supporting potential interactions of vaccine candidates with DCs in vivo.Our previous work has demonstrated the efficacy of antigen-specific tolerogenic immunotherapies employing peptide-MHC-II-based nanomedicines[12][13][14][15]. These therapeutics, containing tissue-specific autoantigenic epitopes, have successfully reprogrammed autoantigenexperienced activated CD4+ T-cells into IL-10-secreting T-regulatory type-1 cells (TR1).…”

Biomaterial Strategies for Selective Immune Tolerance: Advances and Gaps

“…An additional possibility is that these could be invariant natural killer T lymphocytes (iNKT cells), which have recently been demonstrated to be reprogrammable for tolerance. [ 38 ] This work highlights how a suppressive drug—rapamycin—can be focused to a less broadly suppressive effect through particle delivery, as these effects were localized to where particles were distributed and taken up. While this approach was protective against autoinflammation, the claim of tolerance would be more supported with delivery of antigen and analysis of antigen‐specific populations.…”

Transforming growth factor-β promotes the postselection thymic development and peripheral function of interferon-γ-producing invariant natural killer T cells

“…These cells patrol the sinusoidal space to protect against invading pathogens such as the spirochete Borrelia burgdorferi , the causative agent of Lyme’s Disease, and viral infection such as Hepatitis C Virus. (Crosby and Kronenberg, 2018; Thomas et al, 2011; Umeshappa et al, 2022). Chronic activation of iNKT cells is associated with disease severity in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) (Crosby and Kronenberg, 2018; Syn et al, 2012; Syn et al, 2010).…”