Multi-omics analysis of SIV-specific CD8+ T cells in multiple anatomical sites

TL;DR

This study explores the relationship between the location and genetic makeup of CD8+ T cells targeting SIV and their gene activity, finding no strong link to location but identifying differences in gene activity between animals that control the virus and those that don't.

Contribution

The study provides a comprehensive multi-omics analysis of SIV-specific CD8+ T cells across tissues, revealing transcriptional differences associated with viral control.

Findings

No distinct transcriptional profiles were found for CM9-specific CD8+ T cells across different anatomical sites.

Posttreatment controllers showed enriched pathways related to cellular activation compared to animals with progressive infection.

Differences in only a few cellular pathways were observed between CD8+ T cells found in multiple sites and those in a single site.

Abstract

CD8+ T cells exert immunological pressure against immunodeficiency lentiviruses. In previous studies, we examined the TCR repertoire of CD8+ T cells specific for a single SIV immunodominant epitope, Gag-CM9, throughout SIV infection or after vaccination, and across multiple anatomic sites. We identified both tissue specific TCR sequences and TCRs shared by multiple anatomical sites. Here we use single cell RNA sequencing to evaluate if the tissue localization or TCR sequence of a CM9-specific CD8+ T cell corresponds with unique transcriptomics. CM9-specific CD8+ T cells were sorted from blood, lymph nodes, spleen, and liver from SIV infected rhesus macaques with progressive SIV infection and in animals who spontaneously control SIV replication after cessation of antiretroviral therapy. The cells were processed through a single cell sequencing protocol, creating a TCR amplified library and an RNA gene expression library corresponding to individual cells. Gene set enrichment analysis revealed no distinct transcriptional profiles for CM9 specific CD8+ T cells between different anatomical sites and between cells with shared or tissue specific TCRs. Similarly, no clear transcriptional profiles were associated with clonotypes which were shared across individual animals. However, CM9 specific CD8+ T cells from posttreatment controllers did exhibit enrichment of pathways associated with cellular activation compared to progressively infected animals, suggesting that altered transcription in distinct cellular pathways in antigen specific CD8+ T cells may associate with viral control. Together, these studies represent a thorough analysis of the relationship between anatomical and clonal origin, and the transcriptional profile of antigen specific CD8+ T cells and unravel pathways that may be important for CD8+ T cell mediated control of SIV replication.

Virus-specific CD8+ T cells against human immunodeficiency virus (HIV), or, in nonhuman primate models, simian immunodeficiency virus (SIV), are thought to contribute to the antiviral response in acute infection. Virus-specific CD8+ T cells are observed in blood and multiple tissues, with some CD8+ T cell clones observed in a single anatomical site. Currently, it is unknown whether the anatomical site or tissue specificity of a CD8+ T cell clone contributes to the transcriptional phenotype of the cell. Here, we used a single-cell multi-omics approach to evaluate the transcriptional phenotype of virus-specific CD8+ T cells in blood and multiple tissues. We observed no association between the anatomical site and the transcriptional phenotype of the virus specific CD8+ T cells and observed differences in only a couple of cellular pathways between cells found in multiple anatomical sites and those found in just one site. We did identify specific pathways with differential expression between animals able to control viral infection and those with progressive infection. This study represents an in-depth analysis of the clonal origin, anatomical location, and transcriptional phenotype of virus specific CD8+ T cells and contributes to the understanding of the CD8+ T cell response in chronic viral infection.

Figures