, according to investigators.
These finding suggest that gamma delta T17 cells could be a target for novel cell-based therapies against liver diseases, reported lead author Yanan Wang, PhD, of Shandong University, Jinan, China, and colleagues.
“Gamma delta T cells are located in mucosal tissues and other peripheral lymphoid tissues and are considered to act as the first line of defense within the immune system,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “Several studies have reported that IL-17A produced by gamma delta T cells plays a critical role in host defense after Listeria monocytogenes [infection] in the liver. However, in those studies, the details of the phenotypes, dynamic changes, proliferation activity, and cytokine production of the responding gamma delta T cell populations in the overall process of hepatic infection are unclear, and how they accumulated into the infection sites has not been elucidated.”
To address this knowledge gap, Dr. Wang and colleagues conducted a series of experiments involving gamma delta T cells from murine liver samples.
First, using single-cell RNA-sequencing (scRNA-seq), the investigators identified six clusters of hepatic gamma delta T cells.
“[This first step] revealed the unique gene expression characteristics and indicated the possible important roles in immune responses of hepatic gamma delta T17 cells,” they noted.
Next, the investigators measured expression of CD44 and CD27 in liver gamma delta cells.
“Expression of CD44 and CD27 has been used to distinguish IL-17A–, interferon gamma–producing, and other subsets of gamma delta T cells in the thymus, lymph nodes, lungs, and other peripheral lymphoid tissues,” they wrote.
These efforts revealed three subsets of hepatic gamma delta T cells, of which CD44hiCD27– gamma delta T cells were most abundant. Further analysis revealed expression profiles consistent with liver residency.
The next phases of the study characterized the immune roles of hepatic gamma delta T cells.
A comparison of Listeria monocytogenes infection in wild-type versus T-cell antigen receptor knockout mice, for example, showed that knockout mice had significantly more weight loss than did wild-type mice, greater bacterial load in the liver, and shorter survival times.
“As expected, the proportion and absolute numbers of gamma delta T cells in the liver of wild-type mice increased at day 3 and reached a peak at day 7 after infection,” the investigators wrote. “These data suggested that hepatic gamma delta T cells proliferated after infection and contributed to Lm clearance.”
Parabiosis experiments showed that the increased number of CD44hiCD27– gamma delta T cells in the livers of Listeria monocytogenes-infected mice were due to migration and proliferation of liver-resident gamma delta T cells instead of circulating gamma delta T cells. A transwell assay revealed that Kupffer cells and monocyte-derived macrophages promoted migration of CD44hiCD27– gamma delta T cells upon infection.
“Our study provides additional insight into liver-resident lymphocytes and will aid in targeting such tissue-resident lymphocyte populations to promote local immune surveillance,” the investigators concluded.
The study was supported by grants from the National Natural Science Foundation of China and the Shandong Provincial Natural Science Foundation. The investigators disclosed no conflicts of interest.
