Background
Gamma-delta (gd) T cells are enriched in liver and barrier tissues compared to the peripheral blood and aid in the response to gut-derived antigens and tissue homeostasis. They are depleted from the blood during HIV infection, yet what happens to them and the importance of the effect are not well characterized. We hypothesized that gd-T cells may be involved in liver dysfunction during HIV infection.
Methods
Livers from uninfected infant rhesus macaques (SIV-, n=5) and infant macaques chronically infected with SIV (SIV+, n=5) were subjected to GeoMx digital spatial profiling (DSP) to evaluate SIV-associated transcriptional changes within distinct zones of the liver lobule, including changes that indicate enrichment of immune cell populations. Fixed tissue sections were immunostained for periportal (near portal tracts) and pericentral (near central veins) zones. Eighty segments were placed based on immunostaining, profiled using the whole transcriptome atlas and analyzed with linear mixed models, gene set enrichment analysis (GSEA), and mixed cell deconvolution with SpatialDecon algorithm.
Results
DSP identified >100 up and downregulated genes in SIV+ vs SIV- infant macaque livers as well as effects specific to periportal vs. pericentral zones. Genes upregulated in SIV+ livers were associated with inflammation, the type I interferon response and oxidative stress. Deconvolution identified increases in cholangiocytes, liver sinusoidal endothelial cells, non-inflammatory macrophages, and gd-T cells. gd-T cells were the most significantly altered immune cell subset in SIV+ infants. Stress-responsive gd-T cells-1 were increased only periportally while phosphoantigen-responsive gd-T cells-2 were increased periportally and even more so pericentrally. The pericentral zone also experienced strong downregulation of biological oxidation genes (NES -3.68), including those within the glutathione S transferase (eg. GSTP1 (FDR 0.0001)) and cytochrome P450 (eg. CYP39A1 (FDR 1.28E-06)) pathways.
Conclusions
gd-T cells are enriched in the livers of infant macaques infected with SIV and experiencing high viral loads. gd-T cells-1 and gd-T cells-2 are differentially affected by lobule zone, suggesting these subsets may respond to distinct stimuli or exert distinct effects in the SIV+ liver. Ongoing studies are investigating the relationship between accumulation of these cells and other zone-specific transcriptional changes.
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