bims-nastce 2022-02-13 papers

Dev Cell. 2022 Feb 07. pii: S1534-5807(22)00004-1. [Epub ahead of print]57(3): 398-414.e5

Temporal analyses of postnatal liver development and maturation by single-cell transcriptomics.

Yan Liang, Kota Kaneko, Bing Xin, Jin Lee, Xin Sun, Kun Zhang, Gen-Sheng Feng.

The postnatal development and maturation of the liver, the major metabolic organ, are inadequately understood. We have analyzed 52,834 single-cell transcriptomes and identified 31 cell types or states in mouse livers at postnatal days 1, 3, 7, 21, and 56. We observe unexpectedly high levels of hepatocyte heterogeneity in the developing liver and the progressive construction of the zonated metabolic functions from pericentral to periportal hepatocytes, which is orchestrated with the development of sinusoid endothelial, stellate, and Kupffer cells. Trajectory and gene regulatory analyses capture 36 transcription factors, including a circadian regulator, Bhlhe40, in programming liver development. Remarkably, we identified a special group of macrophages enriched at day 7 with a hybrid phenotype of macrophages and endothelial cells, which may regulate sinusoidal construction and Treg-cell function. This study provides a comprehensive atlas that covers all hepatic cell types and is instrumental for further dissection of liver development, metabolism, and disease.

Keywords: construction of metabolic zones; endothelial cells; functional maturation of liver; hepatocyte heterogeneity; interaction of macrophages; postnatal liver development; single cell transcriptomics

DOI: https://doi.org/10.1016/j.devcel.2022.01.004

Immunology. 2022 Feb 08.

Adipose invariant NKT cells interact with CD1d-expressing macrophages to regulate obesity-related inflammation.

Masashi Satoh, Misao Iizuka, Masataka Majima, Chizuru Ohwa, Akito Hattori, Luc Van Kaer, Kazuya Iwabuchi.

Obesity is accompanied by and accelerated with chronic inflammation in adipose tissue, especially visceral adipose tissue (VAT). This low-level inflammation predisposes the host to the development of metabolic disease, most notably type 2 diabetes. We have focused on the capacity of glycolipid-reactive, CD1d-restricted natural killer T (NKT) cells to modulate obesity and its associated metabolic sequelae. We previously reported that CD1d knockout (KO) mice are partially protected against the development of obesity-associated insulin-resistance, and these findings were recapitulated in mice with an adipocyte-specific CD1d deficiency, suggesting that NKT cell-adipocyte interactions play a critical role in exacerbating disease. However, many other CD1d-expressing cells contribute to the in vivo responses of NKT cells to lipid antigens. In the present study, we examined the role of CD1d expression by macrophages (Mϕ) to the development of obesity-associated metabolic inflammation using LysMcre-cd1d1f/f mice where the CD1d1 gene is disrupted in a Mϕ-specific manner. Unexpectedly, these animals contained a higher frequency of T-bet+ CD4+ T cells in VAT with increased production of Th1-cytokines that aggravated VAT inflammation. Mϕ from mutant mice displayed increased production of IL-12p40, suggesting M1 polarization. These findings indicate that interactions of CD1d on Mϕ with NKT cells play a beneficial role in obesity-associated VAT inflammation and insulin resistance with a sharp contrast to an aggravating role of CD1d on another type of antigen presenting cell, dendritic cells.

DOI: https://doi.org/10.1111/imm.13447

J Immunol. 2022 Feb 07. pii: ji2100842. [Epub ahead of print]

Liver Environment-Imposed Constraints Diversify Movement Strategies of Liver-Localized CD8 T Cells.

Harshana Rajakaruna, James H O'Connor, Ian A Cockburn, Vitaly V Ganusov.

Pathogen-specific CD8 T cells face the problem of finding rare cells that present their cognate Ag either in the lymph node or in infected tissue. Although quantitative details of T cell movement strategies in some tissues such as lymph nodes or skin have been relatively well characterized, we still lack quantitative understanding of T cell movement in many other important tissues, such as the spleen, lung, liver, and gut. We developed a protocol to generate stable numbers of liver-located CD8 T cells, used intravital microscopy to record movement patterns of CD8 T cells in livers of live mice, and analyzed these and previously published data using well-established statistical and computational methods. We show that, in most of our experiments, Plasmodium-specific liver-localized CD8 T cells perform correlated random walks characterized by transiently superdiffusive displacement with persistence times of 10-15 min that exceed those observed for T cells in lymph nodes. Liver-localized CD8 T cells typically crawl on the luminal side of liver sinusoids (i.e., are in the blood); simulating T cell movement in digital structures derived from the liver sinusoids illustrates that liver structure alone is sufficient to explain the relatively long superdiffusive displacement of T cells. In experiments when CD8 T cells in the liver poorly attach to the sinusoids (e.g., 1 wk after immunization with radiation-attenuated Plasmodium sporozoites), T cells also undergo Lévy flights: large displacements occurring due to cells detaching from the endothelium, floating with the blood flow, and reattaching at another location. Our analysis thus provides quantitative details of movement patterns of liver-localized CD8 T cells and illustrates how structural and physiological details of the tissue may impact T cell movement patterns.

DOI: https://doi.org/10.4049/jimmunol.2100842

Front Immunol. 2021 ;12 757379

Murine CXCR3+CXCR6+γδT Cells Reside in the Liver and Provide Protection Against HBV Infection.

Yanan Wang, Yun Guan, Yuan Hu, Yan Li, Nan Lu, Cai Zhang.

Gamma delta (γδ) T cells play a key role in the innate immune response and serve as the first line of defense against infection and tumors. These cells are defined as tissue-resident lymphocytes in skin, lung, and intestinal mucosa. They are also relatively abundant in the liver; however, little is known about the residency of hepatic γδT cells. By comparing the phenotype of murine γδT cells in liver, spleen, thymus, and small intestine, a CXCR3+CXCR6+ γδT-cell subset with tissue-resident characteristics was found in liver tissue from embryos through adults. Liver sinusoidal endothelial cells mediated retention of CXCR3+CXCR6+ γδT cells through the interactions between CXCR3 and CXCR6 and their chemokines. During acute HBV infection, CXCR3+CXCR6+ γδT cells produced high levels of IFN-γ and adoptive transfer of CXCR3+CXCR6+ γδT cells into acute HBV-infected TCRδ-/- mice leading to lower HBsAg and HBeAg expression. It is suggested that liver resident CXCR3+CXCR6+ γδT cells play a protective role during acute HBV infection. Strategies aimed at expanding and activating liver resident CXCR3+CXCR6+ γδT cells both in vivo or in vitro have great prospects for use in immunotherapy that specifically targets acute HBV infection.

Keywords: HBV infection; chemotaxis; liver; liver-resident γδT cells; residency; γδT cells

DOI: https://doi.org/10.3389/fimmu.2021.757379