bims-nastce 2021-11-07 papers

Front Immunol. 2021 ;12 719954

Regulatory T-Cell Therapy in Liver Transplantation and Chronic Liver Disease.

Angus Hann, Ye H Oo, M Thamara P R Perera.

The constant exposure of the liver to gut derived foreign antigens has resulted in this organ attaining unique immunological characteristics, however it remains susceptible to immune mediated injury. Our understanding of this type of injury, in both the native and transplanted liver, has improved significantly in recent decades. This includes a greater awareness of the tolerance inducing CD4+ CD25+ CD127low T-cell lineage with the transcription factor FoxP3, known as regulatory T-Cells (Tregs). These cells comprise 5-10% of CD4+ T cells and are known to function as an immunological "braking" mechanism, thereby preventing immune mediated tissue damage. Therapies that aim to increase Treg frequency and function have proved beneficial in the setting of both autoimmune diseases and solid organ transplantations. The safety and efficacy of Treg therapy in liver disease is an area of intense research at present and has huge potential. Due to these cells possessing significant plasticity, and the potential for conversion towards a T-helper 1 (Th1) and 17 (Th17) subsets in the hepatic microenvironment, it is pre-requisite to modify the microenvironment to a Treg favourable atmosphere to maintain these cells' function. In addition, implementation of therapies that effectively increase Treg functional activity in the liver may result in the suppression of immune responses and will hinder those that destroy tumour cells. Thus, fine adjustment is crucial to achieve this immunological balance. This review will describe the hepatic microenvironment with relevance to Treg function, and the role these cells have in both native diseased and transplanted livers.

Keywords: Treg; cell therapy; cirrhosis; immunity; liver; rejection; transplant

DOI: https://doi.org/10.3389/fimmu.2021.719954

Nat Rev Immunol. 2021 Nov 05.

Immune cell-mediated features of non-alcoholic steatohepatitis.

Thierry Huby, Emmanuel L Gautier.

Non-alcoholic fatty liver disease (NAFLD) includes a range of hepatic manifestations, starting with liver steatosis and potentially evolving towards non-alcoholic steatohepatitis (NASH), cirrhosis or even hepatocellular carcinoma. NAFLD is a major health burden, and its incidence is increasing worldwide. Although it is primarily a disease of disturbed metabolism, NAFLD involves several immune cell-mediated inflammatory processes, particularly when reaching the stage of NASH, at which point inflammation becomes integral to the progression of the disease. The hepatic immune cell landscape is diverse at steady state and it further evolves during NASH with direct consequences for disease severity. In this Review, we discuss current concepts related to the role of immune cells in the onset and progression of NASH. A better understanding of the mechanisms by which immune cells contribute to NASH pathogenesis should aid the design of innovative drugs to target NASH, for which current therapeutic options are limited.

DOI: https://doi.org/10.1038/s41577-021-00639-3

Diabetes. 2021 Nov 04. pii: db210659. [Epub ahead of print]

Regulatory T cells control Effector T cell Inflammation in Human Prediabetes.

Rui Liu, Gabriella H Pugh, Erin Tevonian, Katherine Thompson, Douglas A Lauffenburger, Philip A Kern, Barbara S Nikolajczyk.

A disparate array of plasma/serum markers provide evidence for chronic inflammation in human prediabetes, a condition that is most closely replicated by standard mouse models of obesity and meta-flammation. These remain largely non-actionable, and contrast with our rich understanding of inflammation in human type 2 diabetes. New data show that inflammatory profiles produced by CD4+ T cells define human prediabetes as a unique inflammatory state. Regulatory T cells (Tregs) control mitochondrial function and cytokine production by CD4+ effector T cells (Teff) in prediabetes and type 2 diabetes by supporting Th17 or Th1 cytokine production, respectively. These data suggest that Treg control of Teff metabolism controls inflammation differentially in prediabetes compared to type 2 diabetes. Queries of genes that impact mitochondrial function and/or pathways leading to transcription of lipid metabolism genes identified the fatty acid importer CD36 as highly expressed in Tregs but not Teff from prediabetes subjects. Pharmacological blockade of CD36 in Tregs from prediabetes subjects decreased Teff production of the Th17 cytokines that differentiate overall prediabetes inflammation. We conclude Tregs control CD4+ T cell cytokine profiles through mechanisms determined, at least in part, by host metabolic status. Furthermore, Treg CD36 uniquely promotes Th17 cytokine production by Teff in prediabetes.

DOI: https://doi.org/10.2337/db21-0659

J Leukoc Biol. 2021 Nov 03.

Single-cell profiling of T lymphocytes in deficiency of adenosine deaminase 2.

Zhijie Wu, Shouguo Gao, Naoki Watanabe, Sai Batchu, Sachiko Kajigaya, Carrie Diamond, Lemlem Alemu, Diego Quinones Raffo, Xingmin Feng, Patrycja Hoffmann, Deborah Stone, Amanda Ombrello, Neal S Young.

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic vasculitis syndrome caused by autosomal-recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1). Vasculitis, vasculopathy, and inflammation are dominant clinical features of this disease; the spectrum of manifestations includes immunodeficiency and lymphoproliferation as well as hematologic manifestations. ADA2 is primarily secreted by stimulated monocytes and macrophages. Aberrant monocyte differentiation to macrophages and neutrophils are important in the pathogenesis of DADA2, but little is known about T lymphocytes in this disease. We performed combined single-cell RNA sequencing and single-cell TCR sequencing in order to profile T cell repertoires in 10 patients with DADA2. Although there were no significant alterations of T cell subsets, we observed activation of both CD8+ and CD4+ T cells. There was no clonal expansion of T cells: most TCRs were expressed at basal levels in patients and healthy donors. TCR usage was private to individual patients and not disease specific, indicating as unlikely a common pathogenic background or predisposition to a common pathogen. We recognized activation of IFN pathways as a signature of T cells and STAT1 as a hub gene in the gene network of T cell activation and cytotoxicity. Overall, T cells in DADA2 patients showed distinct cell-cell interactions with monocytes, as compared with healthy donors, and many of these ligand-receptor interactions likely drove up-regulation of STAT1 in both T cells and other immune cells in patients. Our analysis reveals previously undercharacterized cell characteristics in DADA2.

Keywords: T lymphocytes; deficiency of adenosine deaminase 2; single-cell RNA sequencing

DOI: https://doi.org/10.1002/JLB.5A0621-314R